Inflammation in cancer: therapeutic opportunities from new insights.

In recent years, AI has gained significant popularity. With the advancement of deep learning and the availability of extensive imaging databases, AI-based computer-aided diagnostic (CAD) systems—which incorporate machine learning (ML), deep learning (DL), and artificial neural networks (ANN)—are increasingly being used to standardize and improve the evaluation of medical imaging. AI models have been used to identify inflammatory and immune cells in cancer tissues. For instance, deep learning techniques have been employed to detect tumor-infiltrating lymphocytes (TILs), which could serve as a potential prognostic marker for testicular germ cell tumors [ 439 ]. Deep convolutional neural networks based on supervised learning have been used to quantify the biomarkers of immune cells in the lung cancer microenvironment [ 440 ]. TILs densities and spatial structures can be analyzed using deep learning on pathology images, providing insights into the tumor-immune microenvironment [ 441 ]. Deep learning supervised by antibodies was utilized to quantify tumor-infiltrating immune cells, an emerging prognostic biomarker in breast cancer samples [ 442 ]. AI-based pathology served as a biomarker for progression-free survival in patients treated with atezolizumab and bevacizumab for hepatocellular carcinoma [ 443 ]. Identifying PLA2G1B, a gene crucial for lipid metabolism and inflammation, suggests it may serve as a preventive marker for lung cancer through bioinformatics and machine learning methods [ 444 ]. Artificial intelligence has recently emerged as a powerful and promising tool for developing anti-tumor medications more quickly, affordably, and effectively [ 445 ]. Due to the crucial role of TLR4 in pro-inflammatory responses, and considering the costly, time-consuming, and labor-intensive nature of traditional drug design approaches, novel TLR4 modulators identified through artificial intelligence and computer-assisted drug design show great promise and have demonstrated positive results [ 446 ]. Due to their high selectivity and low toxicity, anti-inflammatory peptides (AIPs) have shown greater therapeutic potential against inflammatory diseases compared to small compounds. Additionally, machine learning plays a crucial role in predicting peptides [ 447 ]. Artificial intelligence solutions for endoscopy-based cancer evaluation hold great promise for the future. However, the application of these models in clinical practice faces several challenges, including the need for more robust validation studies and overcoming regulatory hurdles. At the same time, AI facilitates data-driven decision-making, helping to expedite drug discovery and development while reducing failure rates. Additionally, AI-powered precision medicine allows doctors to tailor early therapies to the individual needs of each patient.

It is now evident that inflammatory cells and related inflammatory pathways significantly influence tumor growth. However, several issues still need to be addressed. 1) In the absence of an external carcinogenic agent, can inflammation itself lead to neoplasia? While various studies have suggested that inflammation can cause cancer without the presence of exogenous carcinogens, evidence shows that more DNA mutations were observed in a mouse model of bowel inflammation lacking IL-10 when exposed to external carcinogens [ 448 ], and more powerful proof is required to make such a disclosure. 2) Due to the dual role of inflammatory molecules, such as inflammasomes and interleukins, in cancer development and progression, it is important to consider the question about whether we can suppress tumor growth by shifting the balance between “bad” inflammation and “good” inflammation? The adaptive, humoral, and innate immune systems all play integral roles in the complex relationship between local and systemic inflammation and tumor growth. Therefore, triggering an effective anti-tumor adaptive immune response is crucial and requires careful attention. Recently, the use of bromodomain and extra-terminal domain (BET) protein inhibitors (iBET) has been reported to induce cell death and reduce the aggressiveness of oral squamous cell carcinoma (OSCC) [ 449 ]. iBET protects mice from pancreatic inflammation caused by LPS and the resulting cytokine storm, while also inhibiting cell proliferation in pancreatic cancer [ 450 ]. Another promising approach is to restore a balanced host response by normalizing the inflammatory network. This involves reducing high levels of pro-inflammatory cytokines and other tumor-promoting characteristics of infiltrating cells while increasing the levels of anti-inflammatory cytokines. 3) Do sex steroid hormones play a role in the interplay between inflammation and cancer? The occurrence of tumors varies between genders due to differing sex hormones. Analyzing the interaction between these hormones and inflammation in cancer development could enhance the treatment of hormone-related cancers, such as breast, lung, ovarian, cervical, and prostate cancers. Recent studies have shown that Treg cells, which play a crucial role in managing immune responses and reducing tissue inflammation, are more abundant in male visceral adipose tissue (VAT) compared to females. These differences in Treg cell populations are influenced by the tissue environment and shaped by sex hormones, which help to decrease inflammation in adipose tissue [ 451 ]. Considering the widespread use of selective androgen receptor modulators and selective estrogen receptor modulators like tamoxifen, understanding the interaction between sex hormones, inflammation, and cancer will significantly influence the clinical treatment of cancer.

A growing tumor’s inflammatory component may involve various leukocyte types, such as neutrophils, dendritic cells, macrophages, eosinophils, mast cells, and lymphocytes. These leukocyte types can produce a wide range of cytokines, as well as cytotoxic mediators like reactive oxygen species, serine and cysteine proteases, MMPs, and membrane-perforating agents, as well as soluble mediators of cell death like TNF-α, interleukins, and IFNs [ 269 ]. The detailed information about the inflammatory cells and molecules they secret are summarized and shown in Fig. 1 . And the pro- or anti-tumor effect of these inflammatory molecules are also summarized and shown in Fig. 2 and Fig. 3 . TNFα antibodies or inhibitors such as infliximab are undergoing phase 2 clinical trials in breast and renal cell cancer [ 270 ]. Chemokine receptor antagonists like bicyclam plerixafor are now in clinical use in non-Hodgkin lymphoma and multiple myeloma [ 271 ]. Trabedtedin as the cytotoxic drug to tumor-associated macrophages and circulating monocytes, has been used to treat soft-tissue sarcoma and ovarian cancer [ 272 ]. Fibroblast plays an important role in tumor development, and inhibitors of the fibroblast growth factor receptor have been studied in various tumors [ 273 ]. Fig. 1 The detailed information about the inflammatory cells and molecules they secret. The inflammatory cells include NK cell, monocyte, T cell, neutrophil, eosinophil, mast cell, macrophage, dentritic cell, basophill, plasma cell and B cell. NK cell secretes several kinds of interleukin (IL), interferon (IFN), tumor necrosis factors (TNF), transforming growth factors (TGF), colony-stimulating factor (CSF) and lymphotoxin alpha (LT-α); monocyte secrets several kinds of ILs, IFN, TNF, C-X-C motif) ligand (CXCL) and interferon-inducible protein-10 (IP-10) induced protein; T cell secrets several kinds of ILs, IFN, TNF, TGF, macrophage colony-stimulating factor (M-CSF), receptor activator of nuclear factor-kappa B ligand (RANKL), macrophage inflammatory protein (MIP) and LT-a; neutrophil secrets several kinds of ILs, TNF-a and MIP; eosinophil secrets IL-4, IL-5, MCDF and monocyte chemoattractant protein (MCP); mast cells secrets several kinds of ILs; macrophage secrets several kinds of CXCLs and ILs, TGF-b, TNF, IFN, CSF, vascular endothelial growth factor A (VEGF A), macrophage-derived chemokine (MDC) and MIP; dendritic cell secrets macrophage secrets several kinds of ILs, CX3CL1, IFN, RANKL, CSF, thymus and activation-regulated chemokine (TARC), MDC, MIP and IP-10 induced protein; basophill secrets MCP and several kinds of ILs; plasma cell secrets TGF-β, TNF-α and several kinds of ILs; B cell secrets several kinds of ILs, LT-α, RANKL, TGF-β, IFN-α and MIP Fig. 2 The the pro-tumor effect of these inflammatory molecules are summarized. A Inflammatory molecules which are involved in promoting proliferation, invasion, migration and metastasis are summarized. B Inflammatory molecules which contributes to angiogenesis, epithelial-messenchymal transition, lymph angiogenesis and drug resistance are summarized. C Inflammatory molecules which participates in promoting tumor-related inflammation, malignant progress and tumor recurrence, inhibiting cancer cell death, increasing the motility of cancer cells, promoting tumor growth, enhancing radiation resistance and promoting tumorigenesis. D Inflammatory molecules which contribute to promoting osteolysis and immunosuppression, enhancing tumor immune tolerance, promoting the occurrence of precancerous lesions, culture promoting tumor microenvironment, promoting immune-escape, enhancing adhesion and promoting the stemness of cancer cells Fig. 3 The anti-tumor effect of these inflammatory molecules are summarized. A Inflammatory molecules which are involved in enhancing radiation efficacy, suppressing migration and malignant progression of tumor, inhibiting angiogenesis, lymph angiogenesis and stemness, promoting synergistic apoptosis and enhancing drug sensitivity are summarized. B Inflammatory molecules which contributes to inhibiting inflammation, promoting immunity and tumor cell lysis, preventing immune escape, reducing epithelial-messenchymal transition and promoting cancer cell apoptosis. C Inflammatory molecules which participates in restraining movement, suppressing occurrence, driving cell senescence, inhibiting adhesion and driving non-apoptotic cellular death. D Inflammatory molecules which contribute to suppressing invasion, inhibiting metastasis, restraining growth and inhibiting proliferation The detailed information about the inflammatory cells and molecules they secret. The inflammatory cells include NK cell, monocyte, T cell, neutrophil, eosinophil, mast cell, macrophage, dentritic cell, basophill, plasma cell and B cell. NK cell secretes several kinds of interleukin (IL), interferon (IFN), tumor necrosis factors (TNF), transforming growth factors (TGF), colony-stimulating factor (CSF) and lymphotoxin alpha (LT-α); monocyte secrets several kinds of ILs, IFN, TNF, C-X-C motif) ligand (CXCL) and interferon-inducible protein-10 (IP-10) induced protein; T cell secrets several kinds of ILs, IFN, TNF, TGF, macrophage colony-stimulating factor (M-CSF), receptor activator of nuclear factor-kappa B ligand (RANKL), macrophage inflammatory protein (MIP) and LT-a; neutrophil secrets several kinds of ILs, TNF-a and MIP; eosinophil secrets IL-4, IL-5, MCDF and monocyte chemoattractant protein (MCP); mast cells secrets several kinds of ILs; macrophage secrets several kinds of CXCLs and ILs, TGF-b, TNF, IFN, CSF, vascular endothelial growth factor A (VEGF A), macrophage-derived chemokine (MDC) and MIP; dendritic cell secrets macrophage secrets several kinds of ILs, CX3CL1, IFN, RANKL, CSF, thymus and activation-regulated chemokine (TARC), MDC, MIP and IP-10 induced protein; basophill secrets MCP and several kinds of ILs; plasma cell secrets TGF-β, TNF-α and several kinds of ILs; B cell secrets several kinds of ILs, LT-α, RANKL, TGF-β, IFN-α and MIP The the pro-tumor effect of these inflammatory molecules are summarized. A Inflammatory molecules which are involved in promoting proliferation, invasion, migration and metastasis are summarized. B Inflammatory molecules which contributes to angiogenesis, epithelial-messenchymal transition, lymph angiogenesis and drug resistance are summarized. C Inflammatory molecules which participates in promoting tumor-related inflammation, malignant progress and tumor recurrence, inhibiting cancer cell death, increasing the motility of cancer cells, promoting tumor growth, enhancing radiation resistance and promoting tumorigenesis. D Inflammatory molecules which contribute to promoting osteolysis and immunosuppression, enhancing tumor immune tolerance, promoting the occurrence of precancerous lesions, culture promoting tumor microenvironment, promoting immune-escape, enhancing adhesion and promoting the stemness of cancer cells The anti-tumor effect of these inflammatory molecules are summarized. A Inflammatory molecules which are involved in enhancing radiation efficacy, suppressing migration and malignant progression of tumor, inhibiting angiogenesis, lymph angiogenesis and stemness, promoting synergistic apoptosis and enhancing drug sensitivity are summarized. B Inflammatory molecules which contributes to inhibiting inflammation, promoting immunity and tumor cell lysis, preventing immune escape, reducing epithelial-messenchymal transition and promoting cancer cell apoptosis. C Inflammatory molecules which participates in restraining movement, suppressing occurrence, driving cell senescence, inhibiting adhesion and driving non-apoptotic cellular death. D Inflammatory molecules which contribute to suppressing invasion, inhibiting metastasis, restraining growth and inhibiting proliferation As the means of communication for immune cells and non-immune cells, interleukins play important roles in the occurrence and development of tumors. Their importance as a target and therapeutic agent is demonstrated by the growing number of clinical trials that are presently ongoing. While the results of clinical trials are not satisfactory. Interleukin-6 monoclonal antibodies have been studied in phase 2 and 3 clinical trials in ovarian and renal cancer [ 274 ]. Anti-interleukin-6 receptor antibody-like tocilizumab successfully treats cachexia in lung cancer patients [ 275 ]. Treated with IL1R antagonists enhances the antitumor effect of gemcitabine and 5-fluorouracil [ 276 ]. More details regarding the function of interleukins and underlying mechanisms in cancer are provided in Table 1 . Table 1 The role and mechanisms of interleukins in cancer Interleukin Receptor Cancer types Promote/inhibit Mechanisms References IL-37 IL-1R8, IL-1R5 Colon cancer Promote Promotes colitis-related carcinogenesis through SIGIRR-mediated cytotoxic T cell dysfunction Wang Z et al., 2022 Pancreatic cancer Promote Drives gemcitabine resistance through negative feedback signal of IL-37/STAT3/HIF-1α Zhao T et al., 2020 Skin cancer Promote Inhibits tumor immune surveillance by regulating CD103( +) DCs and establishing a relationship between metabolism and immunity Ceng F et al., 2023 Gallbladder cancer Inhibit Inhibits the EMT induced by HIF-1α Wu T et al., 2018 Renal cancer Inhibit Inhibits IL-6/STAT3 signal transduction Jiang Y et al., 2015 Cervical cancer Inhibit Inhibits proliferation and invasion by suppressing STAT3 Wang S et al., 2015 Lung cancer Inhibit Inhibits migration, invasion and proliferation, and promotes apoptosis through IL-6/STAT3 pathway and Bcl-2, NEDD9 and cyclin D1 Deng Y et al., 2018 IL-36α, IL-36β and IL-36γ IL-1R6, IL-1R3 Oral squamous cell carcinoma Promote Stimulates proliferation of cells with high IL-36R expression, and promotes migration of cells with low IL-36R expression Li Z et al., 2024 Colorectal cancer Promote Induces proliferation by promoting the expression of different genes involved in the IL-17/IL-23 axis Baker J et al., 2023 Liver cancer Inhibit Inhibits the proliferation,activity and migration of HCC in vitro Song Y et al., 2023 IL-2 sIL-2Rα, IL-2/IL-15Rβ–γc, IL-2Rα, IL-2/IL-15Rβ–γc Gastric cancer Promote Mediates the impairment of T cell function Tsubono M et al., 1990 Pancreatic cancer Inhibit Inhibits tumor growth by enhancing the immune function of spleen lymphocytes Zhang J et al., 2009 Inhibits lymph node metastasis by suppressing the expression of VEGF-D mRNA Tang R et al., 2009 IL-4 IL-4Rα–γc, IL-4Rα, IL-13Rα1 Pancreatic cancer Promote Promotes cancer progression, invasion and angiogenesis by enhancing the ability of TIM-derived cathepsin Shi J et al., 2021 Lung cancer Promote Increases cells invasion, migration and vascular remodeling by promoting the differentiation of M0 into M2 macrophages Zhag Y et al., 2024 Liver cancer Promote Enhances the radiation resistance byactivating ERK pathway Liu Y et al., 2023 IL-7 IL-7Rα–γc, sIL-7Rα prostatic cancer Promote Stimulates invasion and migration through AKT/NF-κB pathway Qv H et al., 2016 Breast cancer Inhibit Activates CD8 + T cells and stimulates IFNγ- secretion Yuan C et al., 2014 Hepatocellular carcinoma Inhibit Reshapes the immune system by improving T cell function and antagonizing immunosuppression network Zhang S et al., 2024 Colon cancer Inhibit Amplifies TIL in tumor lesions Maeurer M et al., 1997 Non-small cell lungcancer Inhibit Reduces tumor proliferation by changing cell surface molecular expression and enhancing anti-tumor reactivity Sharma S et al.,1996 IL-9 IL-9R–γc Liver cancer Promote Increases proliferation by driving the expression ofCCL20 and STAT3; induces the occurrence and metastasis through AKT, β catenin and vimentin Gerlach K et al., 2019 Lung cancer Promote Promotes autonomous cells growth, malignant cell transformation and better adhesion through JAK/STAT3 Gerlach K et al., 2019 Enhances tumor growth Pajulas A et al., 2023 Bladder cancer Promote Promotes tumor immune escape by reducing the cytotoxicity of CD8( +) T cells and NK cells Zhou Q et al., 2020 Gastric cancer Inhibit Enhances the function of CD8( +) T cells Fang H et al., 2020 Breast cancer Inhibit Eliminates the metastatic potential bycontrolling extracellular matrix remodeling and cell contractility Das S et al., 2021 IL-15 IL-15, IL15Rα + IL-2, IL-15Rβ–γc Colon cancer Inhibit Enhances the cytotoxicity of TIL Chen Z et al., 2010 IL-21 IL-21R–γc Lung cancer Inhibit Inhibits tumor growth by increasing the cytotoxicity of NkG2D CAR-NK cells Zhang Y et al., 2024 IL-3 IL-3Rα–βc Pancreatic cancer Inhibit Mediates CD4( +) T-eff reaction in IL-3 (-/-) Zaidi N et al., 2019 IL-5 IL-5Rα–βc Bladder cancer Promote Enhances migration and invasion through MMP-9/NF-κB/AP-1 pathway mediated by ERK1/2 Li O et al., 2013 Colon cancer Promote Promotes cell growth by enhancing the effect of IGF-II Makins R et al., 2005 Esophageal cancer Promote Acts as an PAX2 metastasis effector Liu P et al., 2015 Lung cancer Inhibit Blocks metastasis by reducing endothelial barrier permeability through Cd3 T cells Li F et al., 2020 Rectal cancer Inhibit Contributes to host defense and releases their toxic granular proteins by activating eosinophils Tajima K et al., 1998 Pancreatic cancer Promote Stimulates the migration and activation via STAT5 signaling Gitto S et al., 2020 IL-6 IL-6Rα–p130 (classic), sIL-6Rα–gp130 (trans) Prostatic cancer Promote Promotes cell growth through JAK-STAT signaling Lou W et al., 2000 Promotes the occurrence by providingTh2 cytokine environment and up-regulating genes related to cell proliferation and angiogenesis Feurino L et al., 2007 Breast cancer Promote Inhibits apoptosis and drives cell proliferation and invasion through JAK-STAT signaling Manore S et al., 2022 Ovarian cancer Promote Promotes adhesion and invasion through Ras/MEK/ERK and PI3K/AKT pathways Wang D et al., 2016 Breast cancer Promote Promotes the development of BrCAIL-6 by down-regulating HIC1 through paracrine or autocrine signal Sun X et al., 2020 Colorectal cancer Inhibit Promotes the activities of macrophage and lymphokine-activated killer cell Turano M et al., 2021 IL-11 IL-11Rα–p130 (classic), sIL-11Rα–gp130 (trans) Cervical cancer Promote Mediates radiation-resistance through PI3K/AKT signaling pathway Sun R et al., 2021 Pancreatic cancer Promote Activates AKT, ERK and STAT3 signaling Jaclyn K et al., 2014 Gastric cancer Promote Increases the activation of STAT3 Zhou R et al., 2019 IL-31 IL-31Rα–OSMRβ Liver cancer Promote Drives hepatocytes to develop into LCSC by obtaining dryness and stimulates their growth and malignant progress Yuan C et al., 2021 Breast cancer Inhibit Increases the activity of cytotoxic T cells and decreases the levels of CD4( +) T cells, MDSC and tumor-associated macrophages Kan T et al., 2020 IL-10 IL-10Rα,IL-10Rβ Lung adenocarcinoma Promote Down-regulates STAT1 activity by enhancing the expression of SOCS1 and SOCS3 induced by IFN-γ Gao Y et al., 2020 Gastric cancer Promote Drives immunity to escape from microenvironment Zhang H et al., 2022 Carcinoma of colon Inhibit Inhibits cell growth by suppressing STAT3 pathway Won D et al., 2011 Salivaryadenoc-arcinoma Inhibit Induces TNF-driven apoptosis Skrypnyk M et al., 2024 IL-19 IL-20Rα,IL-20Rβ Breast cancer Promote Enhances tumor development and affects the clinical outcome through JAK/STAT signaling Sofi S et al., 2023 Directly promotes tumor proliferation, migration and indirectly provides microenvironment for tumor progress Chen Y et al., 2013 Lung cancer Promote Enhances proliferation by stimulatingIL20RB expression and activating JAK1/STAT3 signaling He Y et al., 2022 IL-20 IL-20Rα,IL-20Rβ, IL-22Rα1,IL-20Rβ Oral cancer Promote Increases proliferation, migration, ROS production and colony formation by promoting TNF-α,IL-1β, MCP-1, CCR4 and CXCR4 expression through activating STAT3and AKT/JNK/ERK signaling Xu Y et al., 2012 Prostatic cancer Promote Increases migration and colony formation by activating p38, ERK1/2, AKT and NF-κB signals Xu Y et al., 2015 Breast cancer Promote Enhances proliferation and migration by up-regulating MMP-9, MMP-12, cathepsin k and G Xu Y et al., 2012 Bladder cancer Promote Promotes the migration through MMP-9 protein mediated by ERK Li S et al., 2013 Hepatocellular carcinoma Promote Promotes tumor progress by inducing TGFβ and MMP-9 expression, and phosphorylating JNK/STAT signaling Ding W et al., 2018 IL-22 IL-22Rα1, IL-10Rβ, IL-2Rα2 (also known as IL-22BP) Lung cancer Promote Increases proliferation by activating STAT3 and enhancing the expression of anti-apoptotic B-cell lymphoma 2 Kobold S et al., 2013 Promotes tumor cell survival and drug resistance by up-regulating anti-apoptosis proteins Zhang W et al., 2008 Gastric cancer Promote Promotes invasion through STAT3 and ERK activation Fukui H et al., 2014 Promotes migration and invasion through IL-22R1 /AKT/MMP-9 Ji Y et al., 2014 Breast cancer Promote Promotes proliferation in a STAT3-dependent manner Zhang Y et al., 2020 Ovarian cancer Promote Promotes tumor development Through STAT3 signaling Lei B et al., 2018 Colorectal cancer Promote Promotes proliferation through STAT3 signaling Wu T et al., 2013 Non-small cell lung cancer Promote Confers EGFR-TKI resistance through AKT and ERK signaling Wang X et al., 2019 Pancreatic cancer Promote Promotes proliferation, invasion and migration by stimulating AKT signal transduction Wang X et al., 2020 IL-24 IL-20Rα,IL-20Rβ, IL-22Rα1, IL-20Rβ Lung cancer Inhibit Inhibits proliferation and promotes apoptosis Qi Q et al., 2014 Pancreatic cancer Inhibit Induces apoptosis and CTL to kill cancer cells and produces anti-tumor immunity Xv B et al., 2014 Breast cancer Inhibit Promotes apoptosis and cell arrest in G2/M phase through PI3K/β-catenin signaling Deng L et al., 2020 Colorectal cancer Inhibit Inhibits cell growth by inducing tumorlysis and apoptosis, and stimulating immunity Deng L et al., 2020 Endometrium cancer Inhibit Inhibits proliferation by promoting apoptosis through mitochondrial intrinsic signal pathway Liao S et al., 2020 IL-26 IL-20Rα,IL-10Rβ Non-small cell lung cancer Promote Increases net angiogenic activity and tumor growth by promoting CXCR-2 dependent angiogenesis NumasakI M et al., 2005 Breast cancer Promote Dephosphorylates and down-regulates EphA3 and phosphorylates endoplasmic reticulum induced by EGFR-TKI via AKT and JNK Itoh T et al., 2021 IL-12 IL-12Rβ1,IL-12Rβ2 Lung cancer Inhibit Enhances the cytolytic activity of PBMC on lung cancer cells Hiraki A et al., 2002 Ovarian cancer Inhibit Inhibits cell proliferation Wang J et al., 2006 Promotes the self-renewal of CD133( +) cancer stem cell-like cells Wang D et al., 2017 Oral cancer Promote Promotes proliferation promoting by nuclear trans-activation of RelA Fukuda M et al., 2010 IL-27 and IL-30 (also known as IL-27 subunit p28) IL-7Rα (also known as WSX1)–gp130 Lung cancer Inhibit Reduces proliferation and metastasis through miR-935 Wang T et al., 2019 Ovarian cancer Inhibit Inhibits proliferation by enhancing STAT3 and inhibiting AKT signaling Zhang Z et al., 2016 Cervical cancer Inhibit Restricts angiogenesis by paracrine Zhang B et al., 2017 Prostatic cancer Inhibit Inhibits tumor growth and improves the survival rate of patients Sorrentino C et al., 2019 IL-35 IL-12Rβ2–gp130, IL-12Rβ2, IL-12Rβ2 gp130–gp130, IL-27Rα,IL-12Rβ2 Breast cancer Promote Promotes invasion and metastasis Wang A et al., 2018 Promotes tumor progression by inhibiting proliferation of infiltrating T-conv cells and inducing iTr35 cells Hao S, et al., 2018 Colorectal cancer Promote Inhibits proliferation of T cells and may participate in tumor immune tolerance through STAT1 and STAT3 Ma Y et al., 2016 Lung cancer Promote Inhibits CD4 T cell-mediated immune response Hao Y et al., 2022 Promotes tumor progression by inducing T cell differentiation Zhou A et al., 2021 Prostatic cancer Promote Promotes cell proliferation, tumor angiogenesis and limits the antitumor immune response by increasing the ratio of Tregs to MDSC and decreasing the ratio of CD4 + and CD8 + T cells Zhu J et al., 2020 Pancreatic cancer Promote Promotes tumor growth by enhancing proliferation and inhibitingapoptosis Nicholl M et al., 2014 Colon cancer Inhibit Inhibits migration, invasion, proliferation, colony formation and cancer stem cells by inhibiting β-catenin Zhang J et al., 2017 IL-17A/F IL-17RA,IL-17RC Lung cancer Promote Promotes tumor growth and progressthrough the coordination of immune cells (i.e. macrophages) Ferreira N et al., 2020 IL-17B IL-17RB Breast cancer Promote Promotes tumor resistance to paclitaxel by activating ERK1/2 pathway Laprevotte E et al., 2017 Promotes tumor occurrence through NF-κB mediated anti-apoptosis pathway Huang Z et al., 2014 Lung cancer Promote Promotes metastasis by activating ERK/β- catenin Yang Y et al., 2018 Pancreatic cancer Promote Promotes invasion and the survival of cancer cells through ERK1/2 Wu H et al., 2015 Gastric cancer Promote Enhances proliferation and migrationthrough IL17B activated mesenchymal stem cells Bi Q et al., 2017 Activates IL-17RB/AKT/β-catenin pathway Bi Q et al., 2016 IL-17C IL-17RA,IL-17RE Lung cancer Inhibit Increases the expression of neutrophil chemokine, keratinocyte derived chemokine and macrophage inflammatory protein 2 induced by NTHi and TNF-α Jungnickel Cet al., 2017 Colorectal cancer Promote Promotes cancer development by improving survival rate Song X et al., 2014 Promotes angiogenesis by producing VEGF through STAT3/miR-23a-3p/SEMA6D axis Li Y et al., 2020 IL-17D Unknown Lung cancer Promote Promotes tumor progression via p38 MAPK signaling pathway Li Z et al., 2022 Ovarian cancer Promote Promotes cell growth by changing of MICA expression level Zhang J et al., 2014 Accelerates cell proliferationand enhances migration and invasion by activating NF-κB Fan Y et al., 2024 Breast cancer Promote Exerts immuno-suppressive effect by producing IL-17D Ruan J et al., 2021 IL-25 (also known as IL-17E) IL-17RA,IL-17RB Lung cancer Promote Promotes cisplatin resistance by increasing the major fornix proteins through activating NF-κB Shen W et al., 2019 Colorectal cancer Promote Maintains tumor infiltrating MDSC by promoting IL-C2 Jou E et al., 2022 Breast cancer Inhibit Activates caspase-mediated apoptosis Furuta S et al., 2022 IL-28A and IL-28B IL-28Rα ( IFNLR1), IL-10Rβ Lung cancer Inhibit Inhibits growth and induces apoptosis through STAT1 phosphorylation Tezuka Y et al., 2012 IL-29 IL-28Rα,IL-10Rβ Multiplemyeloma Promote Activates STAT1 and STAT3 Novak A et al., 2008 Pancreatic cancer Inhibit Overexpresses P21 and Bax Balabanov D et al., 2019 Cervical cancer Inhibit Inhibits proliferation and promotes apoptosis by up-regulating the expression of TRAILR1 Ha L et al., 2024 Skin cancer Inhibit Increases MHC class 1,P21 and Rb protein Romee R et al., 2014 Lung cancer Inhibit Promotes cell arrest and apoptosis by up-regulating p21 through STAT Barrera L et al.,2015 Gastric cancer Inhibit Decreases Bcl-2 and caspase cascade Gao Z et al., 2014 Induces a possible NK cell-mediated immune response Bu X et al., 2014 Colorectal cancer Inhibit Increases NK and NK T cell activity Aulino P et al., 2010 Esophageal cancer Inhibit Increases MHC class 1, P21 and Rb protein Li Q et al., 2010 IL-8 (also known as CXCL8) CXCR1, CXCR2 ACkR1/DARC Breast cancer Promote Promotes invasion and migration by promoting Wnt/β-catenin signaling Mou C et al., 2018 Ovarian cancer Promote Enhances invasion and migration by promoting EMT Wang S et al., 2018 Stimulates cell adhesion and invasion by activating PI3K/AKT and Raf/MEK/ERK signaling and increasing MMP-2 and MMP-9 activity and expression Niu X et al., 2013 Bladder cancer Promote Improves drug resistance by maintaining the characteristics of cancer stem cells Zhu K et al.,2014 Renal carcinoma Promote Promotes EMT through PKC/ERK signaling Bi L et al.,2012 Pancreatic cancer Promote Promotes invasion by regulating MMP-2 activity Kuwada Y et al., 2003 Gastric cancer Promote Promotes metastasis through c-Jun and Ets-1 Chen H et al., 2017 Renal carcinoma Promote Induces migration by activating AKT signaling through CXCR2 Bi L et al., 2014 Ovarian cancer Promote Induces chemo-resistance by increasing the expression of MDR1, Bcl-2, Bcl-xL and XIAP, and activating Raf/MEK/ERK and PI3K/AKT signaling Niu X et al., 2012 Cervical cancer Promote Promotes proliferation, invasion and migration by activating ERK and up-regulating MMP-9 Ye K et al., 2022 Promotes the carcinogenic potential by increasing the expression of IL-RA, IL8RB and ERK and decreasing the expression of NUMB Jia L et al., 2018 Prostate cancer Inhibit Promotes proliferation and inhibits apoptosis through STAT3/AKT/NF-κB pathway Guo Y et al., 2017 IL-13 IL-13Rα1,IL-4Rα, IL-13Rα2 Pancreatic cancer Promote Promotes proliferation by enhancing p44/42 MAPK (ERK1/2) phosphorylation and tyrosine and PI3 kinaseactivity Shi J et al., 2021 Colon cancer Promote Promotes malignancy by inducing the expression of 11βHSD2 in an IL-13Rα2-dependent manner Jiang L et al., 2016 IL-14α andIL-14β IL-14R N/A IL-16 CD4 Breast cancer Promote Promotes tumor progression by recruiting immune cells infiltrating into tumors Richmond J et al., 2014 Lung cancer Promote Contributes to the implantation of tumor cells into lung parenchyma Donati K et al., 2017 IL-32 (also known as Nk4) Unknown Lung cancer Promote Promotes immune escape by developing immuno-suppressive microenvironment Zhao S et al., 2024 Cervical cancer Promote Promotes tumor progress by forming a positive regulatory loop with NF-κB/miR-205 Liu J et al.,2024 Pancreatic cancer Promote Regulates downstream molecules and promotes invasion Takagi K et al., 2021 Gastric cancer Promote Increases invasion Tsai C et al., 2014 Colon cancer Promote Creates a favorable environment for tumor growth by up-regulating IL-8, TNF and CCL2 Catalán V et al., 2017 Esophageal cancer Promote Induces polarization of M2 macrophages via FAK/STAT3 pathway Sun Y et al., 2022 Triple negative breast cancer Promote Increases migration and invasion through EMT by up-regulating VEGF-STAT3 pathway Park H et al., 2012 Thyroid cancer Promote Contributes to cell survival by inducing cytokine IL-8 Sloot Y et al., 2019 Multiplemyeloma Promote Produces immuno-suppression and allows tumor growth through NF-κB pathway Yan H et al., 2019 Gastric cancer Promote Inhibits autophagy through PI3K/AKT/mTOR signaling Wang X et al., 2022 Lung adenocarcinoma Promote Promotes migration and invasion by up-regulating NF-κB Zeng Q et al., 2014 Osteosarcoma Promote Stimulates invasion and movement by activating AKT and up-regulating MMP13 Zhou Y et al., 2015 Liver cancer Promote Inhibits apoptosis and increases cell survival by activating NF-κB and p38/MAPK pathways Kang H et al., 2012 Gastric cancer Promote Promotes tumor progression by increasing metastasis through activating AKT, β-catenin and HIF-1α Cai C et al., 2014 Liver cancer Promote Stimulates cell survival and growth by activating and maintaining NF-κB Han X et al., 2019 Lymphoma Promote Stimulates cell proliferation by activating MAPK and NF-κB Hiraku S et al., 2013 Colon cancer Inhibit Inhibits tumor development by promoting the death signal of TNFR1 Yun M et al., 2015 Inhibits dryness and EMT by suppressing STAT3-ZEB1 pathway Bak Y et al., 2016 Colorectal cancer Inhibit Enhances TNFα-mediated apoptosis by up-regulating p32-MAPK signaling Yun M et al., 2023 Thyroid cancer Inhibit Induces caspase-mediated apoptosis Heinhuis B et al., 2015 Melanoma Inhibit Inhibits proliferation and increases apoptosis by up-regulating p21, p53, and TRAILR1 Nicholl M et al., 2016 Pancreatic cancer Inhibit Reduces EMT by inhibiting JAK/ST T3 signal and the expression of EMTmarkers and MMP2, 9 and 7 Bak Y et al., 2016 Skin cancer Inhibit Improves survival rate by increasing the number of tumor-specific CD8 + T cells Gruber T et al., 2020 Bladdercancer Inhibit Inhibits tumor growth by enhancing the cytotoxicity of NK-92 Wu K et al., 2022 Breast cancer Inhibit Increases proliferation and decreases apoptosis Wang S et al., 2015 Cervical cancer Inhibit Inhibits tumor development by inducing the production of pro-nflammatory cytokines and down- regulating E7 and COX2 through negative feedback loop Lee S et al., 2011 IL-34 CSF1R Mastadenoma Promote Promotes epithelial cell transformation Poudel M et al., 2021 Gastric cancer Promote Promotes proliferation and EMT Li C et al., 2022 Colon cancer Inhibit Inhibits cell proliferation and enhances the susceptibility of cells to oxaliplatin-induced death by suppressing ERK1/2 Franze E et al., 2018 Liver cancer Inhibit Inhibits tumor growth and metastasisby inhibiting proliferation and EMT Tian B et al., 2023 IL-1α IL-1R1, IL-1R3 sIL-1R3 Gastric cancer Promote Increases the percentage of S phase fraction of cells, stimulates cell proliferation Furuya Y et al., 2000 Breast cancer Promote Promotes proliferation, invasion or migration Qiu J et al.,2021 IL-1β IL-1R 1, IL-1R3 IL-1R2, IL-1R3, sIL-1R2, sIL-1R3 Gastric cancer Promote Promotes invasion by activating NF-κB and MMP-9 expression Yamanaka, N et al., 2004 Ovarian cancer Promote Increases expression of IL-1β and may lead to early steps of cancer Woolery T et al., 2014 Cervical cancer Promote Promotes proliferation and migration through MEK/ERK signaling pathway Zhang J et al., 2022 Breast cancer Promote Induces a cascade reaction of TP63 subtype ΔNP63α signal, and leads to cisplatin resistance Mendoza-Rodriguez M et al., 2019 Osteosarcoma Promote Enhances tumor growth by regulating NF-κB signaling and miR-376c /TGFA axis Liu B et al., 2017 IL-33 IL1R3, IL-1R4, sIL-1R4 Gastric cancer Promote Promotes invasion and migration by stimulating the secretion of MMP-3 and IL-6 through ST2-ERK1/2 pathway Yu X et al., 2015 Colorectal cancer Promote Promotes cell proliferation through its receptor ST2, and up-regulates COX2 through NF-κB signaling Li Y et al., 2018 Ovarian cancer Promote Promotes cell proliferation and inhibits apoptosis by down-regulating p27, Fas and TRAILR1 in vitro Liu N et al., 2021 Breast cancer Promote Promotes cell transformation and tumorigenesis Cui H et al., 2015 Lung cancer Inhibit Inhibits tumor growth and lung metastasis by promoting proliferation and activation of CD8 T cells and NK cells through NF-κB signaling Yang K et al., 2022 IL-18 IL-1R5 IL-1R7 IL-18BP Lung cancer Promote Enhances metastasis by down-regulating E-cadherin Jiang D et al., 2003 Pancreatic cancer Promote Promotes cell proliferation and movement Sun Q et al., 2020 Colon cancer Inhibit Inhibits tumor growth and prolongs the survival by blocking the secretion of TGF-β and IL-4, increasing the secretion of TIIFN-Y, enhancing its cytotoxicity Chen Z et al., 2010 Enhances the ability of cancer cells to resist T lymphocytes by up-regulating FasL protein Zhang W et al., 2002 Breast cancer Inhibit Inhibits osteolytic bone metastasis Nakata A et al., 1999 Colorectal cancer Inhibit Promotes tumor immune surveillance by up-regulating FasL and death ligand Dupaui J et al., 2015 The role and mechanisms of interleukins in cancer IL-22Rα1, IL-10Rβ, IL-2Rα2 (also known as IL-22BP) IL-27 and IL-30 (also known as IL-27 subunit p28) IL-7Rα (also known as WSX1)–gp130 IL-25 (also known as IL-17E) IL-28A and IL-28B IL-28Rα ( IFNLR1), IL-10Rβ IL-8 (also known as CXCL8) CXCR1, CXCR2 ACkR1/DARC IL-32 (also known as Nk4) Promotes tumor progress by forming a positive regulatory loop with NF-κB/miR-205 IL-1R1, IL-1R3 sIL-1R3 IL-1R 1, IL-1R3 IL-1R2, IL-1R3, sIL-1R2, sIL-1R3 IL-1R5 IL-1R7 IL-18BP As the most effective and widely distributed family of cytokines, IFNs are induced by nucleic acids and related to immunity and vascular. IFNs are composed of type I, II, and III IFNs. Type I IFNs include IFN-α, β, ε, κ, and ω; type II IFNs refer to IFNγ; type III IFNs include IFNγ1, FNγ2, FNγ3 (first called IL-28A, IL-28B, and IL-29) [ 277 ]. After stimulation, they are produced and secreted by body cells, such as T lymphocytes, B lymphocytes, macrophages, fibroblasts, and epithelial cells [ 278 ]. All IFNs activate the transcription of interferon-stimulated genes through the Janus kinase (JAK)/STAT pathway. Generally, JAK1 and JAK2 are activated by type II IFN signaling to cause STAT1 homodimerization, whereas TYK2 and JAK1 are activated by type I and III IFN signaling to cause STAT1-2 heterodimerization and IFN-stimulated gene (ISG) factor 3 (ISGF3) creation [ 277 ]. IFNα and IFNβ, which belong to type I interferons, directly control the transcription of over 100 downstream genes, resulting in direct (on cancer cells) and indirect (through immune effector cells and vasculature) effects on tumors [ 278 ]. Drug development and patient assessment of interferon-directed therapies have benefited from new understandings of the endogenous and external activation of type I interferons in the tumor and its microenvironment. Modulation of the interferon system may further reduce cancer morbidity and death when paired with other efficacious cancer treatment methods or with previous observations. Clinical trials were started by the Finnish National Red Cross and Hans Strander and Kari Cantell using partially purified IFNα, which was made from human blood donor leukocytes in Cantell’s Helsinki laboratory [ 279 ]. Abundant evidence indicated the anti-tumor effects of leukocyte-derived INFα on various metastasis solid tumors and hematological malignancies [ 280 ]. Recombinant INFα2 was the first human immunotherapeutic approved by the FDA for cancer [ 281 ]. However, exogenous INFα2 and IFNβ also lead to systemic adverse effects. The discovery of the molecular and cellular aspects of pathways of induction and action of interferon, such as effects of protein products of interferon-stimulated genes (ISGs), cellular actions of interferons, and endogenous nucleic acid-induced pathways, which may provide new opportunities for enhancing the anti-tumor effect of these cytokines. For example, it has been suggested that RNA is a more powerful transcription inducer of interferons regarding RIG-I (retinoic acid-inducible gene I) or Toll-like receptors (TLR3, TLR7, and TLR8). A TLR3 agonist ARNAX facilitates the effect of immunotherapy on patients [ 282 ]. TLR 3 and 7 agonists induce a hot triple-negative breast cancer immune environment [ 283 ]. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumor-associated macrophages to enhance cancer immunotherapy [ 284 ]. Besides, cytoplasmic protein cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS) binds to DNA and initiates the synthesis of cGAMP, activating the stimulator of interferon genes (STING), then activates the endogenous interferon system [ 279 ], which provides a fresh understanding of how immune effector cells’ endogenous interferon system is activated. And the cGAS-STING pathway plays a fundamental and vital function in identifying immunogenic cancer cells. When the intracellular STING protein is activated, various immunostimulatory molecules are produced, which can lead to the maturation of dendritic cells, the polarization of anti-tumor macrophages, the priming and activation of T cells, the activation of natural killer cells, vascular reprogramming, and/or the death of cancer cells. These processes can result in the immune system eliminating tumors and producing anti-tumor immune memory [ 285 ]. STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma [ 286 ]. STING agonist promotes CAR T cell trafficking and persistence in breast cancer [ 287 ]. cGAS-STING-mediated type I interferon signaling enhances the development of stem cell-like CD8 + T cells by inhibiting Akt activity [ 288 ]. The combination of STING agonists with radiotherapy or chemotherapy can enhance the antitumor effect and reduce the side effects caused by conventional treatments [ 289 , 290 ]. Moreover, co-administering STING agonists with CTLA4 and PD1 antibodies demonstrated a significant survival advantage in a preclinical model of HPV + oral tumors [ 291 ]. The combination of the STING agonist DMAXX and CAR T cell therapy significantly increases the number of CAR T cells [ 287 ]. Recent studies have improved our understanding of the cGAS/STING pathway in cancer treatment, but prolonged STING activation can promote carcinogenesis. Analysis of the TCGA database shows that several cGAS-encoding genes are significantly upregulated in malignant tissues compared to normal controls, indicating that cGAS/STING signaling may be active in these cancers [ 292 ]. Current research indicates that STING can increase the expression of the immune checkpoint indoleamine-2,3-dioxygenase (IDO), which may directly or indirectly reduce T-cell function and numbers, thereby promoting immunological escape [ 293 ]. The enzyme cGAS, found in mitochondria, suppresses ferroptosis and promotes the progression of hepatocellular carcinoma [ 294 ]. These reports suggest that cGAS may be a potential target for cancer interventions. The inhibitory effects of astin C, a novel STING-specific inhibitor, on Trex1/BMDMs highlight the potential of astin C for cancer treatment [ 295 ]. Further research is necessary to evaluate the effectiveness of cGAS-STING pathway inhibition in cancer treatment. The role of IFNs in cancer is complex, based on the time, cells present, total IFN-I signal levels, and the IFNα/β sub-types mediating the effects, frequently producing different results. Additionally, it’s becoming evident that the timing of IFN-I delivery or blockade can have radically different outcomes, illuminating the complex biology at play. More details regarding the function of TLRs and STING and the role of their agonists in cancer are provided in Table 2 and Table 3 respectively. Table 2 The role and mechanisms of Toll-like receptor (TLR) in cancer TLR Expressed cell Cancer types Promote/inhibit Mechanisms References TLR7 B lymphocy te,T lymph ocyte, neuron mature dendritic cell, macro phage Pancreatic cancer Promote Increases cell proliferation and promotes chemo-resistance Grimmig T et al., 2015 Lmiquimod (TLR7 agonist) Breast cancer Inhibit Blocks IL-10 Yusuf N et al., 2014 Basal cell carcinoma Inhibit Modulates immune response Stockfleth E et al., 2003 TLR5 Epithelial cell, dendritic cell, macrophage, fibroblast B lymphocyte Oral cancer Promote Promotes tumor progression Kauppila J et al., 2013 An TLR4 Endothelial cell, fibroblast, liver cell, macrophage, dendritic cell, epithelial cell Oral cancer Promote Enhances invasion Kong Q et al., 2020 Cervical cancer Promote Promotes proliferation and apoptosis resistance partially through Toll-like receptor 4/NF-κB pathway Jiang N et al., 2018 Breast cancer Promote Promotes tumor progression via TLR4/NF-κB/STAT3 signaling Ochi A et al., 2012 Skin cancer Promote Up-regulates immuno-suppressive and pro-inflammatory cytokines and chemokines Sato Y et al., 2009 Lung cancer Promote Promotes migration and counterattack of cells by inducing autophagy Mi-Jeong K et al., 2022 Prostate cancer Promote Promotes tumor cell activation, proliferation, survival and tumor transformation Gonzalez-Reyes S et al., 2011; Huang B et al., 2009 Promotes tumor development by reducing immune function Engblom C et al., 2016; Ugel S et al., 2015 Ovarian cancer Promote Contributes to tumor growth through TLR4-MyD88 signaling Kelly M et al., 2006 Colon cancer Promote Escapes from immune surveillance by inhibiting the functions of T and NK cells Huang B et al., 2005 Gastric cancer Promote Promotes tumor occurrence and progress through NF-κB pathway Yue Y et al., 2011 Intestinal tumor Inhibit Decreases tumors induced by azoxymethane/sodium dextran sulfate Fukata M et al., 2011 Inhibit Silence of TLR4 increases metastasis, and TLR4 induces effective cancer antigen-specific cytotoxic T cell immune response Ahmed A et al., 2013 Prostate cancer Inhibit Initiates innate immunity to invasive pathogens Kundu S et al., 2008; Gonzalez-Reyes S et al.,2011; Huang B et al., 2009 Coli toxin BCG vaccine (TLR-4 agonist) Gastric cancer Inhibit Induces exfoliation and autophagy Galluzzi L et al., 2012 TLR2 Macrophage, dendritic cell, epithelial cell, fibroblast, endothelial cell, B lymphocyte Colon cancer Promote Promotes proliferation, migration, and invasion through PI3K/AKT and NF-κB Wang X et al., 2018 Gastric cancer Promote Increases proliferation and survival of gastric epithelial cells Liu Y et al., 2019; West A et al., 2017; Cui L et al., 2021 Weakens the function of CD8 + lymphocyte Yang H et al.,2014 Promotes tumorigenesis independent of inflammation in STAT3-driven cancer Jenkins B et al., 2012 Breast cancer Promote Promotes tumor progression and resistance to chemotherapy Di Lorenzo A et al., 2022 Oral cancer Inhibit TLR2 deficiency enhances tumor susceptibility by promoting an inflammatory environment Li B et al., 2024 Polysaccharide Krestin (TLR2 agonist) Breast cancer Inhibit Has potent anti-tumor effects via stimulating both innate and adaptive immune pathways Lu H et al., 2011 Bacteria Peptidoglycan (TLR2 agonist) Breast Cancer Promote Promotes invasion and adhesion by targeting Toll-Like receptor 2 in the cancer cells Xie W et al., 2010 Coli toxin BCG vaccine (TLR2 agonist) Gastric cancer Inhibit Induces exfoliation and autophagy Galluzzi L et al., 2012 TLR8 Monocyte, macrophage, dendritic cell, neutrophil Pancreatic cancer Promote Increases cell proliferation and promotes chemo-resistance Grimmig T et al., 2015 TLR9 Dendritic cell, B lymphocyte, macrophage, fibroblast, epithelial cell Skin cancer Promote Enhances invasion and promotes proliferation through activation of NF-κB and Cox-2 and secretion of IL-8, IL-1α (41) and TGF-β (42) Di J et al., 2009 Lung cancer Promote Promotes tumor progression Ren T et al., 2009 TLR3 Dendritic cell, fibroblast, macrophage, epithelial cell, B lymphocyte Lung cancer Promote Promotes migration and counterattack of cells by inducing autophagy Mi-Jeong K et al., 2022 Oral squamous carcinoma Inhibit Promotes apoptosis Luo Q et al., 2012 Table 3 The role and mechanisms of stimulator of interferon genes (STING) in cancer STING Cancer types Promote/Inhibit Mechanisms References STING Ovarian cancer Promote Makes cancer-associated fibroblasts sensitive to platinum chemotherapy by inhibiting CGAS-STING pathway Liu J et al., 2024 Colorectal cancer Promote Promotes proliferation and induces drug resistance by regulating AMPK-mTOR pathway Yao H et al., 2022 Colon cancer Promote Activates reprogrammed tumor-associated macrophages to M1 phenotype and transforms immune cold peritoneal tumor into T cell inflammatory tumor; STING agonists cooperate with PD-1 and/or COX2 blocker to further inhibit carcinogenesis Lee S et al., 2021 Breast cancer Promote Down-regulation of STING reduces cell survival rate and increases the sensitivity of genotoxicity treatment in a cell-independent way Cheradame L et al., 2021 Induces cell survival and immunosuppression by IL-6-mediated STAT3 activation through NF-κB Vasiyani H et al., 2022 Gastric cancer Promote/Inhibit Knocking down STING and activating STING with 2′3'-c-GAMP promote polarization of TAMs into pro-inflammatory subtype, and induce apoptosis through IL6R-JAK-IL24 pathway Miao L et al., 2020 Inhibit Inhibits proliferation, migration and immune escape by activating cGAS-STING/IFN-β Yuan M et al., 2022 Pancreatic cancer Inhibit Produces type I IFN and activates T cells through CD8α + DC Cheng H et al., 2020 Constant stimulation of the cGAS–STING leads to cell death, inhibits tumorigenesis Gulen M et al., 2017 Has anti-tumor impact on TME by producing type I IFN and priming T cells via CD8α + DCs Corrales L et al., 2017 Colorectal cancer Inhibit Weakens the tumorigenesis of colitis-related colorectal cancer by enhancing intestinal epithelial focal death Gong W et al., 2022 Breast cancer Inhibit Promotes the anti-tumor immune response of tumor-specific CD8 + T cells Lu Z et al., 2022 Lewis lung cancer Inhibit Activates the anti-tumor immune response of T cells and inhibits tumor progression Zhang X et al., 2023 Ovarian cancer Inhibit Enhances the anti-tumor activity Zhang J et al., 2020 Prostate cancer Inhibit Induces immune system rejection and eliminates PCa cells Alnukhali M et al., 2024 Skin cancer Inhibit Induces antigen-specific reactive T cells by promoting the transcription of type I IFN through activating TBK1 and enhances the phosphorylation of IRF3 or STAT6 Honda T et al., 2013 Sawada Y et al., 2015 Squamous cell carcinoma of skin Inhibit Enhances the anti-tumor effect by combining with DNA damaging agents Hayman T et al., 2021 Baird J et al., 2018 Liang D et al., 2015 Promotes the activation of NK cells and DC induced by cetuximab Lu S et al., 2018 Adult T cell leukemia/ lymphoma Inhibit Enhances the formation of IRF3-Bax complex and leads to the apoptosis of adult T-cell leukemia/lymphoma Bladé J et al., 2010 Bladder cancer Inhibit Activates cytoplasmic pattern recognition receptor and downstream IFN1 pathway Koti M et al., 2019 DMXAA series (agonist) Pancreatic cancer Inhibit Improves patients’ survival rate and anti-tumor immunity by prompting T cells; reduces tumor size by activating cytolytic T cells Jing W et al., 2019 3′3′-cGAMP (agonist) Pancreatic cancer Inhibit Reduces metastasis and tumor growth, and promotes anti-tumor immune response Lu X et al., 2020 ADU-V19 type (agonist) Pancreatic cancer Inhibit Enhances vaccine immunogenicity, vaccine-specific T cells and anti-tumor immune response Kinkead H et al., 2018 ADU-S100 type (agonist) Pancreatic cancer Inhibit Stimulates immune response by increasing the expression of CXCR3 in T cells Vonderhaar E et al., 2021 CdGMP series (agonist) Pancreatic cancer Inhibit Increases immune cells by activating APC Lorkowski M et al., 2021 Activates endogenous tumor-specific lymphocytes and inhibits metastasis by activating APCs Smith T et al., 2017 IACS-8803 model (agonist) Pancreatic cancer Inhibit Increases lymphoid myeloid population and strengthens checkpoint block Ager C et al., 2021 c-di-AMP (agonist) Breast cancer Inhibit Induces apoptosis Vasiyani H et al., 2021 DMXAA or cGAMP (agonist) Breast cancer Inhibit Enhances the therapeutic effect of Th/Tc17 CAR T cells by up-regulating CXCL9 and CXCL10 to promote the infiltration of CAR T cells into tumor tissues Tian Z et al., 2022 cGAMP (agonist) Breast cancer Inhibit Inhibits tumor growth and prolongs the survival time of pancreatic cancer mouse Da Y et al., 2022 ADU-S100 (agonist) Prostate cancer Inhibit Inhibits tumor progression Esteves A et al., 2021 The role and mechanisms of Toll-like receptor (TLR) in cancer B lymphocy te,T lymph ocyte, neuron mature dendritic cell, macro phage Epithelial cell, dendritic cell, macrophage, fibroblast B lymphocyte Kauppila J et al., 2013 An Endothelial cell, fibroblast, liver cell, macrophage, dendritic cell, epithelial cell Gonzalez-Reyes S et al., 2011; Huang B et al., 2009 Engblom C et al., 2016; Ugel S et al., 2015 Kundu S et al., 2008; Gonzalez-Reyes S et al.,2011; Huang B et al., 2009 Macrophage, dendritic cell, epithelial cell, fibroblast, endothelial cell, B lymphocyte Liu Y et al., 2019; West A et al., 2017; Cui L et al., 2021 Monocyte, macrophage, dendritic cell, neutrophil Dendritic cell, B lymphocyte, macrophage, fibroblast, epithelial cell Dendritic cell, fibroblast, macrophage, epithelial cell, B lymphocyte The role and mechanisms of stimulator of interferon genes (STING) in cancer Liu J et al., 2024 Yao H et al., 2022 Lee S et al., 2021 Cheradame L et al., 2021 Miao L et al., 2020 Yuan M et al., 2022 Cheng H et al., 2020 Gulen M et al., 2017 Corrales L et al., 2017 Gong W et al., 2022 Lu Z et al., 2022 Zhang X et al., 2023 Zhang J et al., 2020 Honda T et al., 2013 Sawada Y et al., 2015 Hayman T et al., 2021 Baird J et al., 2018 Liang D et al., 2015 Lu S et al., 2018 Bladé J et al., 2010 Koti M et al., 2019 Jing W et al., 2019 Lu X et al., 2020 Kinkead H et al., 2018 Vonderhaar E et al., 2021 Smith T et al., 2017 Ager C et al., 2021 Tian Z et al., 2022 Da Y et al., 2022 Esteves A et al., 2021 In the late 1970s, macrophages were discovered to create a cytokine called TNF, also known as TNFα, which can inhibit tumor cell growth and cause tumor regression [ 296 ]. Lymphotoxin, derived from lymphocytes, has a 50% homologous amino acid sequence and binds to the same receptor with TNFα, it came to be called TNFβ [ 297 ]. The TNF superfamily, composed of 19 ligands and 29 receptors, participates in multiple biological functions. Since their role in inflammation, apoptosis, proliferation, invasion, angiogenesis, metastasis, immune, and others, TNF superfamily members were promising targets for drug development. Numerous investigations showed TNF superfamily members to be a kind of strong inflammatory cytokines that both stimulate complicated immune responses and have anti-tumor properties. TNF superfamily actions can be both advantageous and dangerous. On the one hand, TNF acts as the major mediator of cancer-related inflammation, and many antagonists against the TNF family and their receptors have been approved by the FDA, and some of these are already undergoing clinical testing. For example, anti-TNF treatment (infliximab) enhanced the effects of chemotherapy in colon cancer treatment [ 298 ]. On the other hand, TNF can cause cancer cell death, which makes it a possible cancer therapy. As the first cytokine to be employed for cancer treatment, TNFα has been used in the clinic for the treatment of soft tissue sarcoma [ 35 ] and melanoma [ 36 ]. However, reducing TNF’s toxicity is a major task before TNF can be administered consistently. The advancement of TNF-α therapy in the future will depend on reducing systemic therapy’s toxicity and raising TNF-α dosages to increase the direct tumor response. On the other hand, through indirect tumor effects, the use of innovative modes of action may improve safety and efficacy. More details regarding the function of interleukins in cancer are provided in Table 4 . Table 4 The role and mechanisms of tumor necrosis factors (TNF) in cancer TNF Cancer types Promote/Inhibit Mechanisms References TNF-α Gallbladder cancer Promote Autocrine mechanisms Zhu, G et al.,2014 Cervical cancer Promote Increases the expressions of TNF-alpha Li, J et al.,2018 Pancreatic cancer Promote Higher expression in the serum of patients with metastatic disease Karayiannakis, A et al.,2001 Colorectal cancer Promote Increases distant tumor metastasis Li, Z et al.,2017 Rectal cancer Promote Contributes to distant tumor metastasis Li, Z et al.,2017 Breast cancer Promote Promotes tumor growth through the positive feedback loop of TNFR1/NF-κB (and/or p38)/p-STAT3/HBXIP/TNFR1 Cai, X et al.,2017 Breast cancer Inhibit Shows cytotoxic effects against MCF-7 cells Ghandadi,M et al.,2017 Ovarian cancer Inhibit Overcomes the resistance of PTX MIZUTANI,Y et al.,1994 Overcome the resistance of CDDP MIZUTANI,Y et al.,1993 Inhibits H-3-thymidine uptake by PBMC Hassan, M et al.,1999 Prostate cancer Inhibit Inactivates the NF-κB signaling pathway Wang, M et al.,2020 Breast cancer Inhibit Drives cells to non-apoptotic cellular death via RIP1, activation of JNK and ROS production MIZUTANI,Y et al.,1993 Elevates induction of cellular death, increases or reduces CXCR4 expressions, decrease BCSCs population Abdolvand M et al.,2023 Gastric cancer Paracrine TNF-α Ma, G et al.,2013 TNF-β Non-cardiac gastric cancer Promote The G/A + A/A genotype frequencies were significantly higher in patients with intestinal gastric cancer Zheng, W et al.,2019 Colorectal cancer Inhibit Suppresses TNF-β-stimulated NF-κB signaling Buhrmann,C et al.,2019 CD40L Colorectal cancer Inhibit Infects tumor cells and expresses CD40L; have dose-dependent lytic ability against tumor cells Liu, D et al.,2019 Induces the apoptosis Pang, X et al.,2017 Shows immunogenicity on colon 26/CD40L cells Wu, L et al.,2010 Lung cancer Inhibit DC pulsed by the tumor antigens from the reconstitution CD40L enhances its specific immunity capacity Tian, K et al.,2017 Has direct anti-tumor effects against CD40-positive lung cancers Xu, W et al.,2015 Activates human DCs to secrete interleukin-12 Wu, J et al.,2007 Enhances the anti-tumor immunity efficiently Noguchi, M et al.,2001 FasL Colorectal Cancer Promote Causes Duke’s stage, lymph node and liver metastasis Zhang, W et al.,2004 Facilitates hepatic metastasis Li, S et al.,2003 Colon cancer Promote FasL was strong positive in all lymph node metastases of large intestine cancer Zhu, Q et al.,2002 Enhances the ability of cancer cells to counterattack T lymphocytes Zhang, W et al.,2002 Gastric cancer Promote Involves in the pathogenesis and the immune escape and in the degree of differentiation Pu, W et a.,2003 Cervical cancer Promote Induces TILs apoptosis Anggraeni, T et al.,2020 Non-small cell lung cancer Inhibit Abrogates counterattack Lin, Y et al.,2013 Lung cancer Inhibit Participates in the induction of cell apoptosis Di, D et al.,2005 CD30L Colon cancer Promote Increases the expression of PD-L1; promotes the up-regulation of PD-1 expression and inhibits their activation, differentiation and ability to secret effector cytokines Wang, X et al.,2020 4-1BBL Prostate cancer Promote Mediates cancer progression to castration-resistant prostate cancer via enhancing expression and function of AR Zhu, H et al.,2019 Colon cancer Inhibit Inhibits proliferation, migration and invasion, and retards tumor growth Ge, Y et al.,2020 Lung cancer Inhibit Decreases cell viability, induces apoptosis and autophagy Ramos-Gonzalez, M et al.,2024 OX40L Liver cancer Inhibit CD4 + and CD8 + T cells were significantly increased in the OX40L mRNA group Deng, Z et al.,2022 Breast cancer Inhibit Inhibits cell growth and up-regulates the key immune molecules Ox40L and 4-1BBL Kaser, E et al.,2022 TNF-related apoptosis-inducing ligand (TRAIL) Lung cancer Promote Inhibits TRAIL-induced apoptosis Li, H et al.,2021 Bladder cancer Inhibit Up-regulates the expression of TRAIL-R1 and TRAIL-R2 Szliszka, E et al.,2009 Augments the cytotoxic effect of TRAIL Szliszka, Ewelina et al.,2011 Enhances the cytotoxic and apoptotic effects of TRAIL Szliszka, E et al.,2012 Inhibits cell proliferation, down-regulates XIAP and modulates tBid and Bax expression Choi, Y et al.,2014 Suppresses tumor growth Zhao, Y et al.,2013 Colon cancer Inhibit Up-regulates TRAIL receptor expression, enhances TRAIL-induced cell death partly via O-glycosylation Semba, M et al.,2022 Pancreatic cancer Inhibit Strengthens the apoptotic signaling pathway Huang, M et al.,2021 Cervical cancer Inhibit Enhances TRAIL-induced apoptosis through increasing the expression of TRAIL-R2 Szliszka, E et al.,2012 Non-small cell lung cancer Inhibit Induces cell death which is dependent on caspase-8 and caspase-3 activation De Miguel, D et al.,2016 Ovarian cancer Inhibit Enhances TRAIL sensitivity or reverses TRAIL resistance Liang, R et al.,2020 Colorectal cancer Inhibit Enhances the activation and apoptosis of ROS-dependent caspases 3/7, promotes the induction of the death receptor 5 Ishaq, M et al.,2015 Enhances caspase-dependent apoptosis induction via both death receptor- and mitochondrial-mediate apoptosis pathways Sophonnithiprasert, T et al.,2015 Breast cancer Inhibit Induces miR-146a expression and suppresses CXCR4-mediated human breast cancer migration Wang, D et al.,2013 LIGHT(TNFSF14) Tongue cancer Promote Enhances proliferation and migration Gao, W et al.,2015 NSCLC Promotes osteolytic bone metastases Brunetti, G et al.,2020 RANKL Oral squamous cell carcinoma Promote Promotes disease recurrence and a cell compartment Grimm, M et al.,2015 Cervical cancer Promote Recruits Tregs by up-regulating CTSS and enhancing the expression of phosphorylated AKT and mTORC Wang, Y et al.,2019 Strengthens the dialogue between cells and regulation of IL-8 secretion Shang, W et al.,2015 NSCLC Promote Activates NF-κB pathway, increases RANKL and M-CSF expression and induces osteoclastogenesis Choi, J et al.,2020 Promotes tumor angiogenesis YU, Z et al.,2009 Breast cancer Promote Promotes migration via the PI3K/AKT-HIF-1α pathway Tang, Z et al.,2011 The inhibition of RANKL sensitizes cancer stem cells to denosumab Cuyas, E et al.,2017 Induces cell migration Tang, Z et al.,2011 Gastric cancer Promote Induces migration partially through the activation of PI3K and MEK signaling Wang, Y et al.,2013 Induces cell migration Wang, Y et al.,2018 TWEAK Pancreatic cancer Promote TWEAK expression rate was higher than that in chronic pancreatitis and normal pancreatic tissues Wei, A et al.,2017 Breast cancer Promote Relates to the metastatic ability Zheng, Y et al.,2008 Ovarian cancer Promote Promotes metastasis via NF-κB pathway activation and VEGF expression Dai, L et al.,2009 Colon cancer Promote Promotes cell proliferation and infiltration Zhang, Y et al.,2014 Ovarian cancer Inhibit Enhances cisplasin sensitivity by regulating apoptosis Ma, N et al.,2013 Promotes macrophage-derived exosomal miR-7 to cell through regulating Dicer Qiu, X et al.,2018 Activates autophagy and enhances the cisplasin sensitivity Wang, W et al.,2013 Colon cancer Inhibit Induces apoptosis Dionne, S et al.,2010 Cervical cancer Inhibit Promotes cell apoptosis Wang, D et al.,2010 APRIL Breast cancer Promote Mediates breast cancer cell stemness Pelekanou, V et al.,2018 Gastric cancer Promote Induces cisplatin resistance via activation of the NF-κB pathway Zhi, X et al.,2015 Colorectal cancer Inhibit Suppresses cell growth and promotes apoptosis Wang, J et al.,2010 BAFF Breast cancer Promote Mediates cell stemness Pelekanou, V et al.,2018 Cervical cancer Inhibit Promotes immunosuppression Ding, J et al.,2023 VEGI Prostate cancer Inhibit Inhibits cellular motility and adhesion Zhang, N et al.,2009 Bladder cancer Inhibit Inhibits cellular motility and adhesion Zhang, N et al.,2010 EDA-A2 Breast cancer Inhibit Is down-regulated in breast cancer via promoter methylation Punj, V et al.,2010 The role and mechanisms of tumor necrosis factors (TNF) in cancer Zhu, G et al.,2014 Li, J et al.,2018 Karayiannakis, A et al.,2001 Li, Z et al.,2017 Li, Z et al.,2017 Cai, X et al.,2017 Ghandadi,M et al.,2017 MIZUTANI,Y et al.,1994 MIZUTANI,Y et al.,1993 Wang, M et al.,2020 MIZUTANI,Y et al.,1993 Abdolvand M et al.,2023 Ma, G et al.,2013 Zheng, W et al.,2019 Buhrmann,C et al.,2019 Liu, D et al.,2019 Pang, X et al.,2017 Wu, L et al.,2010 Tian, K et al.,2017 Xu, W et al.,2015 Wu, J et al.,2007 Zhang, W et al.,2004 Li, S et al.,2003 Zhu, Q et al.,2002 Zhang, W et al.,2002 Pu, W et a.,2003 Anggraeni, T et al.,2020 Lin, Y et al.,2013 Di, D et al.,2005 Wang, X et al.,2020 Zhu, H et al.,2019 Ge, Y et al.,2020 Deng, Z et al.,2022 Kaser, E et al.,2022 Li, H et al.,2021 Szliszka, Ewelina et al.,2011 Choi, Y et al.,2014 Zhao, Y et al.,2013 Semba, M et al.,2022 Huang, M et al.,2021 Enhances TRAIL sensitivity or reverses TRAIL resistance Liang, R et al.,2020 Ishaq, M et al.,2015 Sophonnithiprasert, T et al.,2015 Wang, D et al.,2013 Gao, W et al.,2015 Grimm, M et al.,2015 Wang, Y et al.,2019 Shang, W et al.,2015 Choi, J et al.,2020 YU, Z et al.,2009 Tang, Z et al.,2011 Cuyas, E et al.,2017 Tang, Z et al.,2011 Wang, Y et al.,2013 Wang, Y et al.,2018 Wei, A et al.,2017 Zheng, Y et al.,2008 Dai, L et al.,2009 Zhang, Y et al.,2014 Ma, N et al.,2013 Qiu, X et al.,2018 Wang, W et al.,2013 Dionne, S et al.,2010 Wang, D et al.,2010 Zhi, X et al.,2015 Wang, J et al.,2010 Ding, J et al.,2023 Zhang, N et al.,2009 Zhang, N et al.,2010 Punj, V et al.,2010 The ability to produce in vitro colonies of mature myeloid cells from bone marrow precursor cells after the proliferation and differentiation of these cells was the initial defining characteristic of granulocyte/macrophage colony-stimulating factor (GM-CSF; also known as CSF2), macrophage colony-stimulating factor (M-CSF; also known as CSF1), and granulocyte colony-stimulating factor (G-CSF; also known as CSF3). As the main regulators of granulocyte and macrophage populations, CSF can mobilize stem cells to peripheral blood in sufficient quantities for transplantation, speed up the regeneration of protective white blood cells damaged by chemotherapy, boost anticancer immune responses, and possibly contribute to the development of myeloid leukemias [ 299 ]. More details regarding the function of colony-stimulating factors in cancer are provided in Table 5 . Table 5 The role and mechanisms of granulocyte/macrophage colony-stimulating factor (GM-CSF) in cancer GM-CSF Cancer types Promote/inhibit Mechanisms References GM-CSF Colon cancer Promote Promotes liver metastasis by down-regulating E- cadherin and up-regulating N- cadherin and MMP2 Ding X et al., 2018 Makes cells more resistant to cytotoxic drugs through MAPK/ERK signal and EMT-induced transcription factor ZEB1 Chen Y et al., 2017 Non small cell cancer Promote Promotes carcinogenesis Oshika Y et al., 1998 Large cell carcinoma of lung Promote Stimulates autocrine tumor through leukemia reaction and obvious eosinophilia Lammel V et al., 2012 Breast cancer Promote Promotes the tumor-promoting effect of WAT progenitor cells Reggiani F et al., 2017 The depletion of GM-CSF leads to the decrease of proliferation, invasion and dryness by inhibiting STAT3 phosphorylation and β -catenin signal Shi H et al., 2020 Promotes metastasis through the positive feedback loop between GM-CSF and CCL18 Su S et al., 2014 Gastric cancer Promote Promotes chemotherapy induced- CSCs Xue X et al., 2022 Non-myeloid carcinoma Promote Contributes to cancer recurrence through new angiogenesis Aliper A et al., 2014 Lung cancer Promote Stimulates the growth or invasion of tumors Liu Q et al., 2017 Squamous cell carcinoma of head and neck Promote Increases of tumor recurrence or metastasis Young M et al., 1997 Induces angiogenesis and invasion, and related to immune evasion Tenhuinink W et al., 2023 Prostate cancer Inhibit Promotes the host immune monitoring of dendritic cells Bandyopadhyay S et al., 2008 Improves the efficacy of RM-1 prostate cancer cell vaccine Yin W et al., 2010 Colon cancer Inhibit Regulates immune response Urdinguio R et al., 2013 Inhibits DMH-induced colon cancer in rats Dinc S et al., 2007 Endometrium cancer Inhibit Inhibits tumor growth by interacting with TGF-β1 and regulating the expression of TGF-β1 and TGF-β II receptors Ripley D et al., 2001 Bladder cancer Inhibit Inhibits tumor growth and regresses established tumors by increasing the number of mature DC and up-regulating the expression of IFN- dependent PD-L1 Zhang X et al., 2018 Breast cancer, pancreatic cancer Inhibit Enhances the anti-tumor immunity Antonarakis E et al., 2010 Squamous cell carcinoma of head and neck Inhibit Stimulates the differentiation of dendritic cells, presents tumor antigens and regulates T cell function Tenhuinink W et al., 2023 Colon cancer Inhibit Regulating immune response Urdinguio R et al., 2013 Inhibits DMH-induced colon cancer in rats Dinc S et al., 2007 Laryngocarcinoma Inhibit Enhances the immunogenicity of cancer cells, induces proliferation of tumor infiltrating lymphocytes and the tumor-specific cytotoxicity of cytotoxic T lymphocytes Qiu Z et al., 2001 Esophageal cancer Inhibit Promotes the strong immune response Miyashita T et al., 2008 Inhibits proliferation and migration, induces apoptosis and regulates EMT through JAK2-PRMT5 signaling Zhang J et al., 2017 Ovarian cancer Inhibit Negatively induces myeloid suppressor cells (MDSC) and promotes tumor progression and metastasis Zhang Y et al., 2013 Lung cancer Inhibit Inhibits carcinogenesis by being combined with IL-2 Takahashi K et al., 2000 Inhibits carcinogenesis by being combined with immunotherapy and IL-18 Tian H et al., 2023 Enhances the anti-tumor effect of cisplatin Luo D et al., 2017 Bladder cancer Inhibit Inhibits tumor growth and leads to a significant increase in CD4( +), CD8( +) T cells and CD4( +) Foxp3( +) T cells Peng J et al., 2019 Cervical cancer Inhibit Promotes the anti-tumor response by inhibiting the expression of iNOS and COX-2 in a GM-CSFR independent manner Jiang N et al., 2015 Enhances the anti-tumor immune response wirh nanoparticles loaded with adriamycin and GM-CSF Zhang X et al., 2023 Lewis lung cancer Inhibit Enhances the anti-tumor immunity with the combination of FasL and GM-CSF He M et al., 2008 FRG1 (inhibitor) Breast cancer Inhibit Inhibits metastasis by regulating GM-CSF/MEK-ERK axis Mukherjee B et al., 2022 COX-2 inhibitor (inhibitor) Lung cancer Inhibit Improves the prognosis of lung cancer patients by reducing G-CSF or GM-CSF Nakata H et al., 2003 Kaempferol and quercetin (agonist) Prostate cancer Inhibit Stimulates the immune response by stimulating the production of GM-CSF, and then lead to DC recruitment to the tumor site Bandyopadhyay S et al., 2008 The role and mechanisms of granulocyte/macrophage colony-stimulating factor (GM-CSF) in cancer Ding X et al., 2018 Chen Y et al., 2017 Oshika Y et al., 1998 Lammel V et al., 2012 Shi H et al., 2020 Su S et al., 2014 Xue X et al., 2022 Aliper A et al., 2014 Liu Q et al., 2017 Young M et al., 1997 Tenhuinink W et al., 2023 Bandyopadhyay S et al., 2008 Yin W et al., 2010 Dinc S et al., 2007 Ripley D et al., 2001 Zhang X et al., 2018 Antonarakis E et al., 2010 Tenhuinink W et al., 2023 Dinc S et al., 2007 Qiu Z et al., 2001 Zhang J et al., 2017 Zhang Y et al., 2013 Tian H et al., 2023 Luo D et al., 2017 Peng J et al., 2019 Jiang N et al., 2015 Zhang X et al., 2023 He M et al., 2008 Mukherjee B et al., 2022 Nakata H et al., 2003 Prostate cancer Chemokines are 8–12 kDa proteins that are released and bind to Gai-protein-coupled seven-transmembrane-spanning receptors (GPCRs), also known as classical chemokine receptors, to control directed cell movement (chemotaxis), adhesion, cell orientation, and cell–cell interactions [ 300 ]. Comprising around 50 chemokine ligands, 20 signaling GPCRs, and 4 ACKRs, the chemokine system is crucial for various pathological processes. Cancer cells, tissue-resident cells, and recruited immune cells that express a wide variety of chemokine ligands and chemokine receptors all influence the process of carcinogenesis. Chemokines govern the invasiveness, proliferation, and stem-like characteristics of tumor cells. They also influence neoangiogenesis, neurogenesis, and fibrogenesis in stem cells [ 301 ]. Chemokines play a crucial role in guiding immune cell movement when mounting and subsequently delivering an efficient anti-tumor immune response [ 300 ]. Meanwhile, chemokine systems also contribute to pro-tumorigenic immune responses by controlling immune cells’ location and cellular interactions in lymphoid organs and the tumor microenvironment (TME). Chemokines have been attractive therapeutic targets because of their role in mediating the recruitment of anti-tumorigenic immune cells and supporting their activity within TME. Similarly, inhibiting chemokines that draw in and support immune cells’ suppressive roles is an intriguing avenue for future research to enhance treatment outcomes. Additionally, another therapeutic approach being investigated to enhance responses to cancer therapy is the activation or transduction of chemokine receptors on adoptively transferred anti-tumor T cells, which facilitates their ability to enter deeply into the tumor and license their functioning. Significant advancements in our comprehension of the immune system’s function during carcinogenesis have resulted in the creation of innovative immunotherapeutic methods for treating diverse tumors, which have substantially aided cancer patients. Immunotherapy continues to be one of the most promising medical advancements of the twenty-first century. More details regarding the function of chemokines in cancer are provided in Table 6 . Table 6 The role and mechanisms of chemokines in cancer chemokines Receptor Cancer types Promote/inhibit Mechanisms References CCL1 CCR8 Esophageal cancer Promote Promotes tumor progression through 40 kDa/Akt target of mammalian rapamycin pathway/proline-rich Akt substrate Fujikawa M et al., 2021 Colorectal cancer Promote Promotes chemoresistance through TGF β/NF-κB signaling pathway Li Z et al., 2018 Colorectal cancer Inhibit Negatively regulates the progress of liver metastasis Iwata M et al., 2024 Breast cancer Inhibit Inhibits tumorigenesis, metastasis and chemotherapy resistance by reducing the binding of H3K27Me3 in p65 and CCL1 promoter regions to recruit Tregs Xv Y et al., 2017 Lung cancer Inhibit Inhibits the differentiation of Tregs and the metastasis of lung tumors Wang M et al., 2022 CCL2 CCR2 CCR4 CCR5 Breast cancer Promote Promotes cell survival and invasion in vitro Yao M et al., 2017 Stimulates stem cell-specific spherical phenotype and CSC self-renewal Tsuyada A et al., 2012 Induces proliferation, survival, migration and glycolysis through MET-dependent mechanism Acevedo D et al., 2022 Promotes the growth and cell cycle process through SRC and PKC activation Yao M et al., 2019 CCL2-mediated matrix interaction drives macrophage polarization to increase tumor occurrence Archer M et al., 2023 Tongue cancer Promote Promotes invasion and metastasis through PI3K/AKT pathway Dong Y et al., 2023 Bladder cancer Promote LNMAT1 promotes lymphatic metastasis through CCL2-dependent macrophage recruitment Atala A et al., 2019 Promotes migration and invasion through PKC activation and tyrosine phosphorylation Chiu H et al., 2012 Ovarian cancer Promote Promotes tumor progression through MEK/ERK/ MAP3K19 signaling pathway Liu W et al., 2023 Inhibition of CCL2 enhances the treatment efficiency with paclitaxel and carboplatin Mosan F et al., 2014 Promotes ovarian peritoneal metastasis through p38-MAPK pathway Yasui H et al., 2020 Prostate cancer Promote Promotes the migration of prostate cancer Lin T et al., 2013 Promotes cell survival by inducing mTOR pathway Roca H et al., 2009 Stimulates cell proliferation Loberg R et al., 2006 Promotes bone metastasis Li X et al., 2009 Inhibiting CCL2 activity can enhance the therapeutic response to taxane therapy Qian D et al., 2010 Protects cells from autophagy through phosphatidylinositol 3- kinase /Akt/ survivin pathway Roca H et al., 2008 Cervical cancer Promote Promotes proliferation, migration, invasion and EMT Huang T et al., 2020 Lung cancer Promote Promotes EGFR-TKIs resistant cancer through AKT-EMT pathway Diao Y et al., 2024 Colorectal cancer Promote Plays a key role in tumor promotion by recruiting macrophages and influencing their functions Zhang J et al., 2018 Brain tumor Promote Astrocytes promote migration by secreting C–C motif chemokine ligand 2 (CCL2) Hajal C et al., 2021 Gastric cancer Promote CCL2-SQSTM1 positive feedback loop inhibits autophagy to promote chemotherapy resistance Xv W et al., 2018 Hormone dependent mammary gland Promote Anti-CCL2 or anti-CCL5 therapy inhibits the growth of cancer Svensson S et al., 2015 Negative breast cancer Promote Mediates the metastasis of dysmucin in ER-negative breast cancer Nam J et al., 2006 CCL3 CCR1 CCR4 CCR5 Breast cancer Promote Promotes cell growth, leads to EMT and promotes cell migration and invasion through PI3K-AKT-mTOR pathway Luo A et al., 2020 Inhibit Enhances the chemo-sensitivity of docetaxel by triggering the polarization of pro-inflammatory macrophages Anonymous et al., 2022 Colon adenocarci-noma Promote CCL3 -CCR5 axis promotes migration and invasion through AKT signaling pathway Guan BG et al., 2022 Recombinant Bacteroides fragilis enterotoxin −1 (rBFT-1) promotes proliferation through CCL3-related pathway Xie XL et al., 2021 Promotes proliferation, invasion and migration through TRAF6 and NF-κB Ma XQ et al., 2022 Oral cancer Promote Promotes tumorigenesis by inducing inflammation and angiogenesis, and the recruitment of eosinophils da Silva J et al., 2017 Esophageal squamous cell carcinoma Promote Promotes cell migration and invasion through CCR5 binding and phosphorylation of AKT and ERK, thus promoting the progress and poor prognosis of ESCC Kodama T et al., 2020 Human osteosarco-ma Promote Promotes angiogenesis through the imbalance of miR-374b/VEGF-A axis Liao Y et al., 2016 Increases the expression of MMP-2 and enhances the migration ability Xv C et al., 2013 Glioma Inhibit CCL3 alone or in combination with anti-PD-1 may be an effective immunotherapy Wang X et al., 2024 CCL4 CCR1 CCR2 CCR5 Endometrim cancer Promote Promotes proliferation, invasion and migration by targeting VEGF-A signaling pathway Fu H et al., 2017 Oral squamous cell carcinoma Promote Induces the expression of vascular endothelial growth factor C and lymphangiogenesis through miR-195-3p Lian M et al., 2018 Stimulates the expression of angiopoietin −2 and angiogenesis via MEK/ERK/STAT3 Lu C et al., 2022 Human osteosarco-ma Promote Stimulates migration through the miR-3927-3P/ integrin αvβ3 axis Tsai H et al., 2022 Breast cancer Promote Promotes bone metastasis by mediating the interaction between cancer cells and fibroblasts Sasaki S et al., 2016 CCL5 CCR1 CCR3CCR4 CCR5 Breast cancer Promote Promotes tumor growth and metastasis Yao X et al., 2007 Promotes tumor invasion Pinilla S et al., 2009 Gastric cancer Promote Promotes proliferation, invasion and metastasis of gastric cancer cells Ding H et al., 2016 Gastric cancer cells use CCL5 derived from CD4 + cells to grow and prevent tumor elimination with CD8 + cells Sugasawa H et al., 2008 KLF5 leads to low survival rate and promotes cancer progression by activating CCL5/CCR5 axis Yang T et al., 2017 Prostate cancer Promote Promotes the up-regulation of androgen receptor (AR) and leads to enzalutamide resistance by activating AKT Xiong Z et al., 2024 Lung cancer Promote Promotes the migration of human lung cancer cells Hang C et al., 2009 Pancreatic cancer Promote Promotes migration and invasion Singh S et al., 2018 Colon cancer Promote CCL 5 is involved in cancer progression mediated by tumor-associated dendritic cells through non-coding RNA MALAT-1 Guan Z et al., 2015 CCL6 CCR1 CCR2 CCR5 CCR5 N/A CCL7 CCR1 CCR2 Gastric cancer Promote Inhibition of CCL7 weakens proliferation, migration, invasion and induces apoptosis Chen M et al., 2023 Colon cancer Promote Accelerates the early stage of tumor growth and leads to higher lung metastasis rate Kurzejamska E et al., 2019 Promotes metastasis through ERK-JNK signaling pathway Li Y et al., 2016 Ovarian cancer Promote CCL7-induced invasion needs to express MMP 9 by activating ERK signaling Zheng M et al., 2021 Pancreatic cancer Promote Pancreatic stellate cells promote pancreatic cancer invasion through CCL7/CCR5 axis in hypoxic microenvironment Wu Y et al., 2017 Lung cancer Promote ABCE1 participates in tumor occurrence and progression through CCL7 signaling Wu Z et al., 2018 Lung adenocarci-noma Promote LINC01094/SPI1/CCL7 Axis promotes macrophage accumulation and tumor cell spread in lung adenocarcinoma Wu Z et al., 2022 CCL8 CCR1 CCR2 Breast cancer Promote Promotes metastasis by regulating the tumor-promoting activity of tumor microenvironment and promotes tumor growth by recruiting macrophages Farmaki E et al., 2020 Glioblasto-ma Promote CCL8 secreted by tumor-associated macrophages promotes invasion and dryness through ERK1/2 signal Zang X et al., 2020 Colon cancer Promote Accelerates tumor progression through CCL-8 /CCR5/mTORC1 axis Zhou H et al., 2023 CCL9 CCR1CCR3 Lung cancer Promote Enhances the survival rate of tumor cells in lung before metastasis Yan H et al., 2015 Pancreatic ductal adenocarci-noma Promote Carcinogenic Kras enhances pancreatic ADM through its new downstream target molecule CCL9 to start PDAC supply Liou G et al., 2024 Liver cancer Promote Recruits MDSC to promote tumor growth in mice with orthotopic liver cancer Li B et al., 2023 CCL10 CCR1CCR4 N/A CCL11 CCR2 CCR3 Ovarian cancer Promote Plays an important role in the proliferation and invasion Levina V et al., 2009 Head and neck cancer Promote Cancer-related fibroblasts promote tumor invasion of head and neck cancer through CCL11 and CCR3 signal transduction pathway Huang W et al., 2010 Glioblasto-ma Promote Promotes proliferation, migration and invasion Tian M et al., 2016 Non-small cell lung cancer Promote Activates AKT and ERK signaling and promotes metastasis through epithelial-mesenchymal transition (EMT) Lin S et al., 2021 Colon cancer Promote CCL11 aggravates colitis and inflammation-related colon tumors Polosukhina D et al., 2021 Breast cancer Promote Accelerates tumor growth and induces drug resistance and metastasis Liu Y et al., 2017 Asthma-related inflammation promotes lung metastasis through CCL11-CCR3 pathway Bekaert S et al., 2021 Inhibit CCL11 has anti-tumor effect in BRCA Chen X et al., 2024 Anaplastic large cell lymphoma (ALCL) Promote Increases cell survival rate and proliferation , induces ERK1/2 phosphorylation, induces the expression of anti-apoptosis proteins Bcl-xL and survivin and enhances tumor growth Tomomitsu M et al., 2011 Pancreatic cancer Inhibit Autochemokine-lipolytic signal transduction inhibits CCL11- eosinophil axis to promote tumor progress Bhattacharyya S et al., 2024 CCL12 CCR2 N/A CCL13 CCR2 CCR3 N/A CCL14 CCR1 CCR5 Thyroid cancer Promote CCL14 may be involved in the recurrence of THCA Zhang M et al., 2023 Myeloma Promote Promotes tumor growth and survival signals by activating PI3K/AKT and ERK/MAPK pathways and c-myc Li Y et al., 2015 Pancreatic cancer Promote Up-regulates migration and invasion Messex J et al., 2022 Colon cancer Promote Myeloid suppressor cells promote invasion through CCL15 -CCR1 chemokine axis Itatani Y et al., 2014 MDSCs accumulate and invade the primary cancer through CCL15 -CCR1 chemokine axis, and promotes tumor progression Inamoto S et al., 2015 CCL15 secreted by SMAD4 deficient cells recruited CCR1( +) cells to promote lung metastasis Yamamoto T et al., 2017 Inhibit Inhibits proliferation and invasion by inhibiting the formation of M2-like TAM Li N et al.,2021 Long-chain noncoding RNA CCL14-AS inhibits invasion and lymph node metastasis by regulating MEP1A Li M et al., 2023 Hepatocellu-lar carcinoma Promote Recruits inhibitory monocytes to promote the immune escape and CCL15-CCR1 axis creates a complex tumor-promoting inflammatory microenvironment Liu L et al., 2019 Inhibit Inhibits proliferation and promotes apoptosis by inhibiting the activation of Wnt/β-catenin pathway Zhu M et al., 2019 CCL16 CCR1 CCR2 Hepatocellu-lar carcinoma Promote Promotes tumorigenesis by recruiting M2-like tumor-associated macrophages through CCL16-CCR1 axis Dai Z et al., 2024 Breast cancer Inhibit Inhibits tumor growth and prevents metastasis Guiducci C et al., 2004 CCL17 CCR4 CCR8 Cervical cancer Promote Promotes cell proliferation through JNK and STAT5 signaling pathways Liu L et al., 2015 Colitis- related cancer Promote Promotes tumor occurrence by affecting the composition of intestinal microbiota and reducing cell apoptosis Metzger R et al., 2023 CCL18 CCR8 Breast cancer Promote Induces cytoskeleton aggregation through its receptor and promotes migration Chen J et al., 2014 Promotes angiogenesis and tumor progression Lin L et al., 2015 Induces migration and invasion through PCAF-dependent acetylation Song X et al., 2018 Promotes infiltration and migration through integrin aggregation Chen J et al., 2014 Promotes invasion by inhibiting e-cadherin expression mediated by EZH2 Jia H et al., 2023 Promotes invasion and metastasis, and cancer passes through Annexin A2 Zhao C et al., 2024 Promotes malignant behavior by up-regulating Src/PI3K/Akt signaling mediated by ARF6 Huang X et al., 2022 Promotes metastasis by down-regulating miR98 and miR27b Lin X et al., 2015 Gastric cancer Promote Promotes invasion and migration through ERK1/2/NF-κB signaling pathway Hou X et al., 2016 Human pancreatic ductal adenocarcinoma Promote Accelerates the progress of PDAC by promoting epithelial-mesenchymal transformation, invasion and migration Meng F et al., 2015 Oral cancer Promote CCL18-NIR1 promotes the growth and metastasis by activating JAK2/STAT3 Jiang X et al., 2020 Non-small cell lung cancer Promote Enhances the adhesion of NSCLC cells by activating ELMO1- integrin 1 signal Shi L et al., 2016 Mastocarci-ncma Promote CCL18 derived from TAMs plays a key role in promoting breast cancer metastasis through its receptor PITPNM3 Chen J et al., 2011 Lung cancer Promote Induces epithelial-mesenchymal transition and enhances the invasion potential Ploenes T et al., 2013 Bladder cancer Promote Promotes migration, invasion and EMT by binding CCR8 Liu X et al., 2019 Ovarian cancer Promote As a component of ascites, CCL18 plays an important role in tumor cell migration La D et al., 2016 Enhances invasion, migration and adhesion in vitro Zhang W et al., 2013 Promotes invasion through mTORC2 pathway Wang Q et al., 2016 Prostate cancer Promote The up-regulation of CCL18 may be related to the malignant progress of PCa Chen G et al., 2014 Oral squamous cell carcinoma Promote Stimulates growth and invasion in an autocrine way through Akt activation Jiang X et al., 2016 Esophageal cancer Promote Promotes the malignant progression of tumor by up-regulating the expression of HOTAIR Wang W et al., 2019 CCL19 CCR1 CCR7 Colon cancer Promote Promotes the proliferation, migration and invasion of SW620 cells Lu J et al., 2014 Small cell lung cancer Promote Relates to metastasis and poor prognosis, promotes tumor progression and metastasis and damages the function of CD8 + T cells Liu Q et al.,2021 Gastric cancer Inhibit Enhances the immune effect of mice against gastric cancer Chen Z et al., 2021 Inhibits proliferation, migration and invasion in CCL-19 /CCR7/AIM2 pathway Zhou R et al., 2020 Colon cancer Inhibit Activates the immune system Liu X et al., 2019 Inhibits angiogenesis by promoting miR-206 and inhibiting Met/ERK/Elk-1/HIF-1α/VEGF-A pathway Xv Z et al., 2018 Lung cancer Inhibit Chemically attracts dendritic cells and T lymphocytes, which has anti-tumor effect Hillinger S et al., 2003 Reduces the tumor load through extensive mononuclear infiltration of the tumor Hillinger S et al., 2006 Inhibits tumor growth by promoting local anti-tumor T cell response Cheng H et al., 2018 CCL20 CCR6 Colon cancer Promote Induces proliferation and migration through autocrine HGF-c-Met and MSP-MSPR signaling pathways Nandi B et al., 2021 Pancreatic cancer Promote Promotes migration, epithelial-mesenchymal transformation and invasion Liu B et al., 2016 Breast cancer Promote Reduces the expression of IFN-γ secreted by CD8 + T cells through CCR6 + Tregs Xu L et al., 2010 Recruits immature dendritic cells into tumor tissues to impair immune response Treilleux I et al., 2004 Promotes migration and invasion Kim K et al., 2009 Promotes angiogenesis Lee S et al., 2017 Recombinant human CCL20 induces VEGF expression He H et al., 2017 Promotes angiogenesis Marsigliante S et al., 2016 Recruits macrophages into tumors to promote their growth Lee SK et al., 2017 Up-regulates ABCB1 to promote chemical resistance to taxanes Chen W et al., 2018 Regulates PMN-MDSCs and promotes dryness through CXCL2-CXCR2 pathway Zhang R et al., 2023 CCL21 CCR1 CCR7 Colon cancer Promote Up-regulates P-gp, Bmi-1, Nanog and OCT-4 by up-regulating AKT/GSK-3β/Snail, and promotes the chemotherapy resistance and stem cell characteristics Lu S et al., 2016 Promotes the chemotherapy resistance and stem cell characteristics of CRC cells Lu L et al., 2016 Breast cancer Promote Promotes the migration and proliferation of BC cells Peng J et al., 2023 Lung cancer Promote Triggers migration and invasion through ERK and EMT signaling Zhong G et al., 2017 COPD promotes tumor progress by enhancing the migration of CCL21-dependent cancer cells Kuznar-Kaminska B et al., 2016 Non-small cell lung cancer Promote Promotes invasion and metastasis by changing the intracellular Ca2 + concentration Liu J et al., 2012 Oral squamous cell carcinoma Promote Promotes EMT and enhances the dryness of OSCC through JAK2/STAT3 signaling pathway Chen Y et al., 2020 Pancreatic cancer Promote Promotes tumor progress by inducing angiogenesis and lymphangiogenesis Unver N et al., 2021 Ovarian cancer Promote CCL21 and SPARCL1 may contribute to the drug resistance of ovarian cancer Yin F et al., 2013 Colon cancer Inhibit Inhibits migration and invasion, and weakens their stem cell-like phenotype Rong Y et al., 2017 Lung cancer Inhibit Dome nanocapsules can effectively deliver CCL21 to maintain anti-tumor activity and inhibit tumor growth Kar U et al., 2011 Adenocarci-noma Inhibit Inhibits tumor growth and metastasis Yousefieh N et al., 2009 Non-small cell lung cancer Inhibit CCL21-DC overcomes drug resistance of immunotherapy and produces systemic tumor-specific immunity Salehi-Rad R et al., 2023 Neuroblast-oma Inhibit The new nano-preparation of CCL21 is an effective treatment for neuroblastoma Poelaert B et al., 2020 CCL22 CCR4 Oral cancer Promote Cultivates pre-tumor environment by promoting cell transformation and Treg infiltration Huang Y et al., 2019 Gastric cancer Promote Retinal opacification is a suitable microenvironment for migration, survival and metastasis. The CCL22-CCR4 axis is helpful to this selective permeation process Cao L et al., 2014 Prostate cancer Promote CCL17 and CCL22 promote the migration and invasion of prostate cancer cells by enhancing Akt phosphorylation Maolake Aerken et al., 2017 Lung cancer Promote RANKL-induced chemokines derived from CCL22/macrophages produced by osteoclasts promote bone metastasis Nakamura E et al., 2006 Squamous cell carcinoma of head and neck Promote CCR4/CCL22 promotes lymph node metastasis in head and neck squamous cell carcinoma Takahiro T et al., 2013 CCL23 CCR1 Ovarian cancer Promote Promotes the immunosuppression of TME by inducing depleted T cell phenotype Kamat K et al., 2022 Liver cancer Inhibit Progress of CCL-23 inhibits liver cancer through CCR1/AKT/ESR1 feedback loop Meng J et al., 2021 CCL24 CCR3CCR2B CCR5 Hepatocellu-lar carcinoma Promote CCL24 leads to HCC malignant tumor through RhoB-VEGFA-VEGFR2 angiogenesis pathway Jin l et al., 2017 CCL25 CCR9 Breast cancer Promote Promotes invasion by regulating various EMT markers Zhang Z et al., 2016 Promotes proliferation and up-regulates anti-apoptosis signal transduction Johnson-Holiday S et al., 2011 Ovarian cancer Promote Contributes to migration and invasion Johnson S et al., 2010 Inhibits cisplatin-induced apoptosis and supports the drug resistance Johnson S et al., 2010 Lung adenocarcinoma Promote The expression of CCR9 was positively correlated with tumor size, lymph node metastasis, TNM late stage and overall survival rate Zhong Y et al., 2015 Non-small cell lung cancer Promote CCR9/CCL25 interaction induces migration, invasion, anti-apoptosis and tumorigenesis of NSCLC cells Li B et al., 2015 Induces the tumorigenesis by activating PI3K/Akt pathway Li B et al., 2015 Hepatocellu-lar carcinoma Promote Promotes the migration and invasion of HCC cells by regulating EMT markers Zhang Z et al., 2016 CCR9 enhances proliferation and tumorigenicity Zhang Z et al., 2014 Breast cancer Promote Activates Akt in PI3K-dependent and FAK-independent ways to promote cisplatin resistance in breast cancer cells Johnson-Holiday C et al., 2011 CCL26 CCR3 Pancreatic cancer Promote Promotes the invasion of PDAC by activating PI3K/AKT/mTOR pathway Chen X et al.,2021 Colon cancer Promote Participates in tumor progression by regulating EMT signaling pathway Sun A et al., 2022 Participates in promotion and invasion by stimulating tumor-associated macrophage infiltration LAN Q et al., 2018 CCL27 CCR 10 N/A CCL28 CCR3 Breast cancer Promote Promotes proliferation and inhibits apoptosis, which may be regulated by Bcl-2 Lin F et al., 2013 Promotes tumor progress through ERK/MAPK-mediated anti-apoptosis and metastasis signaling pathway Yang X et al., 2017 Pancreatic ductal adenocarcinoma Promote CCL28 blockade can inhibit tumor growth through tumor-cell-internal and external mechanisms Yan J et al., 2021 Ovarian cancer Promote Hypoxia induces CCL28 series to recruit Treg cells to promote cancer progression through tumor-specific immune paralysis Facciabene A et al., 2012 Lung adenocarcinoma Promote Hypoxia induces CCL28 series to recruit Treg cells to enhance angiogenesis of lung adenocarcinoma Liu B et al., 2021 Hypoxia-induced CCL28 series promotes angiogenesis by targeting CCR3 Huang G et al., 2016 Hepatocellu-lar carcinoma Promote Hypoxia-induced CCL28 series promotes the recruitment of regulatory T cells and tumor growth Ren L et al., 2016 Liver cancer Promote High expression of CCL28 in hypoxic microenvironment promotes migration and invasion Zhou Y et al., 2013 Colon cancer Inhibit Transcription activates CCL28, inhibits M2 polarization of macrophages and prevents immune escape Liu S et al., 2024 Oral squamous cell carcinoma Inhibit CCL28 series-induced RARβ expression inhibits bone invasion of oral squamous cell carcinoma Park J et al., 2019 CXCL1 CXCR2 Gastric cancer Promote Overexpression of CXCL1-1 and its receptor CXCR2-2 promotes tumor invasion Cheng W et al., 2011 CXCL1 promotes tumor growth by activating VEGF pathway Wei Z et al., 2015 Drives cells into the lymphatic system by activating integrin β1/FAK/AKT signaling Wang Z et al., 2017 Colon cancer Promote Enhances metastasis by cell migration, MMP-7 expression and EMT Xv T et al., 2018 Promotes the occurrence and development of colon cancer by activating NF-κB/P300 Zhuo C et al., 2022 TADCs under SW620 condition enhance CSC characteristics with the support of enhancing anchor-independent growth, CD133 expression and aldehyde dehydrogenase activity Xv T et al., 2018 Promotes immune escape through autophagy-mediated MHC-I degradation Kong J et al., 2024 Breast cancer Promote Promotes tumor growth and development Ma K et al., 2018 Promotes breast cancer metastasis by activating NF-κB/SOX4 signaling Wang N et al., 2018 Promotes survival, invasion and tumor progression through CXCR2-dependent mechanism Zou A et al., 2023 Promotes proliferation and migration via AKT/NF-κB signaling pathway Yang L et al., 2015 Cervix cancer Promote Promotes growth and migration in both autocrine and paracrine ways Man X et al., 2022 Oral squamous cell carcinoma Promote Inducement of IL-1 β after CXCL1 stimulates CAFs mediates the invasion of cancer cells Wei L et al., 2019 CXCL1 can transform NOFs into aging CAFs through autocrine mechanism Zhang S et al., 2023 Bladder cancer Promote Promotes tumor recurrence, progression and drug resistance by enhancing invasion Miyake M et al., 2016 Oral cancer Promote Promotes proliferation, migration and invasion of oral cancer cells Zhang S et al., 2023 Pancreatic cancer Promote Fibroblast activation protein α-positive pancreatic stellate cells promote migration and invasion by CXCL1-mediated Akt phosphorylation Editorial O et al., 2021 Ovarian cancer Promote Stimulates tumor growth through epithelial-matrix communication activated by p38 Park G et al., 2021 Adiponectin promotes angiogenesis in ovarian cancer through CXCL1 Ouh Y et al., 2018 Promotes the proliferation and invasion of A2780 cells in vitro Bolitho C et al., 2010 Osteosarco-ma Promote CXCL1 plays a key role in promoting the metastasis of osteosarcoma to the lung Zhang H et al., 2017 Prostate cancer Promote The paracrine axis of CXCL1-1 -LCN2 promotes tumor progress through Src activation and EMT Lu Y et al., 2019 Esophageal squamous cell carcinoma Promote CAF secretes CXCL1-1, which regulates DNA damage in a ROS-dependent manner in esophageal squamous cell carcinoma, thus conferring radiation resistance Yang X et al., 2023 ER negative breast cancer Promote CXCL1-1 stimulates the migration and invasion of endoplasmic reticulum negative breast cancer by activating ERK/MMP2/9 signal axis Yang C et al., 2019 Hepatocellu-lar carcinoma Promote CXCL1 plays a key role in the growth and apoptosis of HCC Han K et al., 2015 Prostate cancer Inhibit Inhibits malignant tumor, limits tumor cells from escaping from primary tumor and strengthens growth stagnation Benelli R et al., 2013 Ovarian cancer Inhibit MiR-27b-5p may inhibit the progression of ovarian cancer by targeting CXCL1 Liu C et al., 2020 CXCL2 Epithelial ovarian cancer Promote CXCL2 plays an important role in platinum tolerance of epithelial ovarian cancer (EOC) Nie S et al.,2021 Colon cancer Promote Promotes tumorigenesis through Gi-2 and Gq/11, and contributes to CSC characteristics Chen M et al., 2019 The adhesion and growth is mediated by CXCL2-CXCR2 signal and α V integrin-dependent adhesion to ECM protein Lepsenyi M et al., 2021 ETTL3 promotes lung metastasis by targeting the m6A-Snail-CXCL2 axis to recruit M2-type immunosuppressed macrophages Ouyang P et al., 2024 Promotes the infiltration of M2 macrophages and metastasis of tumor cells Bao Z et al., 2022 Non-small cell lung cancer Promote CXCL2 contributes to the resistance of ANODINI in NCI-H1975 cells Lu J et al., 2019 Oral squamous cell cancer Promote CXCL2 synthesized by oral squamous cell carcinoma is involved in cancer-related bone destruction Oue E et al., 2012 Gastric cancer Promote Omental adipocytes trigger GC cells to form an invasive phenotype through CXCL2 secretion, induce angiogenesis, cell growth and metastasis Natsume M et al., 2020 Hepatocellular cancer Inhibit Overexpression of CXCL2 inhibits and promotes apoptosis Ding J et al., 2018 Osteosarc-oma Inhibit MiR-532-5p plays an anti-tumor role in OS cells by regulating CXCL2 Ma Y et al.,2020 CXCL3 CXCR2 Prostate cancer Promote Overexpression of CXCL3 type cancer can enhance the carcinogenic potential of prostate Gui S et al., 2016 Uterine cervix cancer Promote Overexpression of CXCL3 promotes the tumorigenic potential of cervix cancer cells pass through MAPK/ERK pathway Qi Y et al., 2019 Pancreatic cancer Promote Promotes metastasis through a novel myofibroblast-hijacked cancer escape mechanism Sun X et al., 2021 Oral squamous cell cancer Promote Overexpression of CXCL3 affects the malignant behavior through MAPK signaling pathway Wong J et al., 2021 Colon cancer Promote Promotes the malignant behavior of tumor cells in an ERK-dependent manner Cheng Y et al., 2023 CXCL4 Not found yet Colon cancer Promote Through the negative immuno-modulatory function of CXCR3, non-platelet derived CXCL4 can be hijacked by cancer cells to escape the host immune system Deng S et al., 2019 Breast cancer Promote Specific CXCL4-CXCL12 heterodimers inhibit migration at least partially by competing for CXCR4 receptors Nguyen K et al., 2021 CXCL5 CXCR1 CXCR2 Ovarian cancer Promote CXCL5 promotes ovarian cancer and achieves cell proliferation by up-regulating the expression of cyclin D1 Jian F et al., 2018 Liver cancer Promote Increases migration and invasion through autocrine and paracrine mechanisms Xv X et al., 2014 Colon cancer Promote Promotes metastasis by activating ERK/Elk-1/Snail and AKT/GSK3β/β-catenin Zhao J et al., 2017 Induces tumor angiogenesis by enhancing the expression of FOXD1 mediated by AKT/NF-κB pathway Chen C et al., 2019 Uterine cervix cancer Promote Contributes to oncogenic potential of Hela uterine cervix cancer cells Feng X et al., 2018 Pancreatic cancer Promote CXCL5 promotes PC cell growth and EMT process Wang Z et al., 2022 Necrotic apoptosis before invasion promotes migration and invasion through CXCL5-CXCR2 axis Ando Y et al., 2020 Breast cancer Promote DDR1/CXCL5 promotes immune infiltration of Tregs and drives tumor growth and metastasis Li H et al., 2023 CXCL5 is sufficient to promote the proliferation and colonization of breast cancer cells in bones Romero-Moreno, R et al., 2019 Increases cancer progression through ERK/MSK1/Elk-1/Snail signaling pathway Xv Y et al., 2013 A S100A14-CCL2/CXCL5 signal axis drives breast cancer metastasis Li X et al., 2020 Cervical cancer Promote Promotes proliferation and migration through ERK signaling pathway and autocrine pathway Chen S et al., 2021 Bladder cancer Promote CXCL5 may promote mitomycin resistance by activating EMT and NF-κB pathways Wang C et al., 2018 CXCL5 is very important for the growth and progress of bladder tumor Zheng J et al., 2014 Promotes migration and invasion through activating PI3K/AKT-induced MMP2/MMP9 up-regulation Gao Y et al., 2015 Prostate cancer Promote Enhances cell migration and EMT through early growth response −1/ snail signaling pathway Guo B et al., 2011 CXCL5 can promote the growth of LNCaP cells by acting on its own receptor CXCR2 Qi Y et al., 2014 Lung cancer Promote Promotes immune escape through autocrine and paracrine mechanisms by up-regulating the chemotaxis of lung cancer and neutrophils Sun D et al., 2024 Promotes proliferation and movement by activating MAPK/ERK1/2 and PI3K/AKT Wang L et al., 2018 Gastric cancer Promote The interaction between TAMs and gastric cancer cells promotes chemotherapy resistance through CXCL5/PI3K/AKT/mTOR pathway Su P et al., 2022 Promotes tumor occurrence by regulating tumor immunosuppression mediated by NF-κB and Wnt/β-catenin signals Liu L et al., 2020 Osteosarcoma Promote Promotes migration and invasion in autocrine- and paracrine-dependent manners Dang H et al., 2017 Glioblasto-ma Promote Promotes the tumorigenesis and angiogenesis through JAK-STAT/NF-κb Mao P et al., 2023 Cholangio- carcinoma Promote Promotes tumor metastasis and recurrence by recruiting infiltrating neutrophils Zhou S et al., 2014 Non-small cell lung cancer Promote A2AR-mediated CXCL5 upregulation on macrophages promotes NSCLC progression via NETosis Lei Q et al., 2024 Lung cancer Inhibit Inhibits tumor immunity by regulating PD-1/PD-L1 signal transduction Xie X et al., 2022 CXCL6 CXCR1 CXCR2 Non-small cell lung cancer Promote CXCL6 promotes the survival and metastasis of non-small cell lung cancer cells by down-regulating miR-515-5p Li J et al., 2018 Hepatocell-ular cancer Promote Activates IFN-γ/p38 MAPK/NF-κB signal and promotes EMT and radiation resistance Li X et al., 2023 Promotes liver invasion through targeting MMP9 Zheng Y et al., 2016 Esophageal squamous cell cancer Promote Enhances the growth and metastasis of ESCC cells in vivo and in vitro Zheng S et al., 2021 Melanoma Promote (GCP)−2/CXCL6 induces angiogenesis and promotes tumor growth Verbeke H et al., 2011 CXCL7 CXCR1 CXCR2 Cholangiocarcinoma Promote Promotes the proliferation and invasion of cholangiocarcinoma cells Guo Q et al., 2017 Breast cancer Promote Promotes invasion, the expression of VEGF-C/D and heparanase Yu M et al., 2010 Secretion of CXCL7 by monocytes promotes the progress of breast cancer Wang Y et al., 2021 The interaction between breast cancer cells and monocytes promotes tumor progression through CXCL7-mediated signal transduction Lin S et al., 2021 Renal-cell carcinoma Promote CXCL7 /CXCR1/2 axis is the key driving factor for the growth of clear cell renal cell carcinoma Grepin R et al., 2014 Pancreatic cancer Promote IFNα- induced BST2 + tumor-associated macrophages promote immunosuppression and tumor growth through ERK-CXCL7 signal Zheng C et al., 2024 Triple negative breast cancer Promote The multiple positive feed-forward loops of MCT-1/IL-6/IL-6R/CXCL7/PD-L1 axis promotes the metastatic niche and immunosuppressive microenvironment Aushia T et al., 2024 CXCL8 CXCR1 CXCR2 Gastric cancer Promote Participates in the immunosuppression microenvironment by inducing PD-L1( +) macrophages Lin C et al., 2019 Colon cancer Promote CXCL8 gene silencing significantly inhibits proliferation and invasion via PI3K/Akt/NF-κB signaling Ma J et al., 2015 CXCL8 upregulates LSECtin through AKT, and promotes proliferation and invasion Fang S et al., 2022 Thyroid cancer Promote Promotes the tumor-promoting effect of TC cells Coperchini F et al., 2024 Ovarian cancer and gastric cancer Promote Promotes peritoneal metastasis Awwad O et al., 2018 CXCL9 CXCR3 CXCR7 Prostate cancer Promote Promotes tumor progress by inhibiting cytokines in T cells Tan S et al., 2018 Ovarian cancer Inhibit Inhibits tumor growth Seitz S et al.,2022 CXCL 10 CXCR2 CXCR3 CXCR4 Breast cancer Promote Promotes proliferation and Tamoxifen-resistant MCF7 cells through AKT pathway Wu X et al., 2020 Induces migration through a novel crosstalk between Cxcr3 and Egfr receptor Tsutsumi E et al., 2022 CXCL10 signal transduction promotes the metastasis of ING4 deficient breast cancer Tsutsumi E et al., 2023 Gastric cancer Promote Targeted autophagy promotes T lymphocyte migration by inducing the expression of CXCL10 Meng Q et al., 2022 Promotes gastric invasive cancer through PI3K/AKT dependent MMP production Zhou H et al., 2016 Colon cancer Promote Enhances metastasis by triggering small GTP enzymes such as RhoA and cdc42 Wang Z et al., 2021 Cervical cancer Promote Promotes M2 polarization of macrophages in tumor microenvironment and enhances proliferation, migration and invasion via activating STAT3/NF-κB/CCL2 signal Li A et al., 2024 Ovarian cancer Inhibit Promotes CTL activation to inhibit ovarian cancer Dong M et al., 2024 Enhances the killing effect of T cells and inhibits angiogenesis Li W et al., 2021 Prostate cancer Inhibit Inhibits proliferation and reduces PSA production by up-regulating CXCR3 receptor Nagpal M et al., 2006 HER2 positive breast cancer Inhibit Induces activation of CD8 ~ + T cells to promote effect of immunotherapy on HER2-positive breast cancer Zhang X et al., 2022 Breast cancer Inhibit controlling the self-regulation of CXCL10 and the characteristics of malignant tumor by mediating NF-κB signaling pathway Jin W et al., 2017 Colon cancer Inhibit Inhibits tumor growth, increases CD8 + T cell infiltration and induces tumor blood vessels to normalize by making colorectal cancer cells overexpressing cetuximab Yan W et al., 2023 Cervical cancer Inhibit Enhances the radiotherapy effect of HeLa cells through cell cycle redistribution Yang L et al., 2012 CXCL 11 CXCR3 Hepatocellular cancer Promote Promotes the proliferation and migration of HCC cells through LINC00152/miR-205-5p/CXCL11 axis Liu G et al., 2022 Squamous cell carcinoma of head and neck Promote Promotes tumor lymph node metastasis Wang X et al., 2021 Colon adenocarcinoma and rectal adenocarcinoma Promote Enhances the infiltration of TAMs into tumor environment, promotes EMT of cancer and promotes tumor metastasis by inducing the expression of TGF-β1 Liu M et al., 2021 Zeng YJ et al., 2016 Renal cancer Promote EP300/CBP promotes proliferation and migration by stabilizing CXCL11 mRNA level Zeng X et al., 2022 Promotes tumor angiogenesis Suyama T et al., 2005 Oral cancer Promote Promotes tumor growth and immune escape Wang X et al., 2021 Promotes early malignant transformation and tumor development Xia J et al.,2011 Promotes the occurrence of precancerous lesions Wang X et al., 2021 Cutaneous melanoma Promote Induces cytoskeleton remodeling and promotes tumor metastasis Kawada K et al., 2004 Breast cancer Promote Activates ERK pathway and enhances tumor invasion Hwang H et al., 2020 Multiple myeloma Promote Activates tyrosine kinase, induces MMP-2 and MMP-9 secretion and promotes tumor growth and metastasis Pellegrino A et al., 2004 Ovarian cancer Promote The high expression of CXCR3-A in endometriosis inhibits cytotoxic T cells and promotes the occurrence of precancerous lesions Furuya M et al., 2007 Furuya M et al., 2011 Basal cell carcinoma Promote Promotes the proliferation of human immortalized keratinocytes and promotes tumor growth Lo B et al., 2010 Thyroid cancer Promote Promotes angiogenesis in metastatic THCA through EGF-EGFR positive feedback loop Liang J et al., 2021 Inhibits proliferation, migration, induces apoptosis, and inhibits tumor growth Fallahi P et al., 2018 Colon cancer Promote Down-regulation of CXCL11 inhibits cell growth and EMT Gao Y et al., 2018 Pancreatic cancer Promote Induces invasion and EMT by activating NF-κB signaling pathway Sun L et al., 2019 Cutaneous melanoma Inhibit Recruits immune cells, promotes bone marrow activation, enhances anti-tumor immune response and inhibit tumor growth Harlin H et al., 2009 Renal cancer Inhibit Has immunosuppressive activity on tumor vasculature and tumor angiogenesis Gacci M et al., 2009 Gastric adenocarcinoma Inhibit Activates CXCR3 and up-regulates PD-L1 expression through STAT and PI3K-Akt pathways, thus improving the effectiveness of immunotherapy Zhang C et al., 2018 Mediates the infiltration of cytotoxic T lymphocytes and inhibit angiogenesis Verbeke H et al., 2012 Activates Th1, promotes M1 polarization in macrophages and inhibits tumor growth Pasini F et al., 2014 Lung cancer Inhibit Induces CD8 T cell infiltration, inhibits angiogenesis and enhances the efficacy of immunotherapy Mitsuhashi A et al., 2021 Bladder Urothelial carcinoma Inhibit Improves the chemosensitivity Zhang Y et al., 2019 CXCL 12 CXCR4 CXCR7 Lung cancer Promote The destruction of CXCL12 inhibits the growth and migration of lung cancer cells Imai H et al., 2010 CXCL12 induces lung cancer cell migration by polarized mtDNA redistribution Ma J et al., 2014 Gastric cancer Promote Promotes distant metastasis by activating CXCR4 Ishigami S et al., 2007 Colon cancer Promote Silencing CXCL12 inhibits proliferation, invasion and angiogenesis by down-regulating MAPK/PI3K/AP-1 signaling Ma J et al., 2018 Pancreatic cancer Promote CXCL12 -CXCR4 promotes the proliferation of pancreas and invades cancer cells Shen B et al., 2014 Breast cancer Promote Signal transduction through CXCL12-CXCR4 is an important for migration Nguyen K et al., 2020 CXCL12-γ was identified as an effective transfer promoter Lei P et al., 2015 Prostate cancer Promote Promotes peripheral invasion of prostate cancer Zhang S et al., 2009 Non-small cell lung cancer Promote The interaction between cancer-associated fibroblasts and tumor epithelial cells through CXCL12/CXCR4 axis promotes tumor proliferation Wald O et al., 2011 Colon cancer Promote Enhances the metastatic potential through PI3K/Akt/mTOR pathway Ma J et al., 2017 Down-regulating CXCR4/CXCL12 axis can reduce cancer growth and metastasis Song Z et al., 2015 The combination of CXCR7 and CXCL12 promotes lung metastasis Wang M et al., 2018 Bladder cancer Promote Enhances immune escape by inhibiting autophagy degradation of PDL1 mediated by P62 Zhang Z et al., 2023 Non-small cell lung cancer Promote CXCL12-CXCR4 biological axis is involved in regulating the metastasis of non-small cell lung cancer Phillips R et al., 2003 Intestinal gastric cancer Promote CXCL12/CXCR7 may be the biological axis of proliferation, invasion and lymph node and liver metastasis Xin Q et al., 2016 Ovarian cancer Promote Cancer-related fibroblasts induce EMT and cisplatin resistance through CXCL12/CXCR4 axis Zhang F et al., 2020 Thyroid carcinoma Promote CXCL12-CXCR4 biological axis plays an important role in the process of thyroid cancer metastasis Wu Y et al., 2012 Ovarian cancer Promote CXCL12 promotes cell invasion by inhibiting the expression of ARHGAP10 Luo N et al., 2020 Cervical cancer Inhibit Inhibits anchorage independent cell growth Yadav S et al., 2016 CXCL 13 CXCR4 CXCR7 Lung cancer Promote Mediates radiotherapy resistance of lung cancer by activating Akt Geng S et al., 2020 Promotes the migration of lung cancer cells Zhao C et al., 2021 Colon cancer Promote Plays a key role in carcinogenesis, tumor development, metastasis and recurrence Qi X et al., 2013 CXCL13-CXCR5 axis promotes growth, migration and invasion through PI3K/AKT Zhu Z et al., 2015 Promotes the occurrence of intestinal tumors by activating epithelial AKT signal Zhao Q et al., 2021 Prostate cancer Promote CXCL13 participates in AR regulating the growth of prostate cancer xenograft in mice Tian Q et al., 2019 Renal-cell carcinoma Promote Promotes proliferation and migration by binding to CXCR5 and activating PI3K/AKT/mTOR signaling Zheng Z et al., 2019 Human osteosarco-ma Promote Promotes migration through phospholipase C β (PLC beta), protein kinase C α (PKC α), c-Src and nuclear factor-κB (NF-κB) Liu J et al., 2020 Breast cancer Promote CXCL13 inhibition causes the decrease of tumor growth via CXCR5/ERK signaling Xv L et al., 2018 Breast cancer Inhibit Triggers effective anti-tumor immunity by attracting immune cells to infiltrate Ma Q et al., 2021 Cervical cancer Inhibit Down-regulation of DNA methylation-dependent CXCL13 may promote tumor occurrence and progress Ma D et al., 2020 CXCL 14 CXCR4 CXCR7 Non-small cell lung cancer Promote CXCL14 promotes metastasis of non-small cell lung cancer through ACKR2-dependent signaling pathway Zhang Z et al., 2023 Breast cancer Promote The CXCL14/ACKR2 pathway is a clinically relevant stimulator of EMT, invasion and metastasis Sjoberg E et al., 2019 Ovarian cancer Promote Up-regulating CXCL14 promotes the proliferation of ovarian cancer cells Li X et al., 2021 Pancreatic cancer Promote CXCL14 significantly increases the invasion of pancreatic cancer cells Wente M et al., 2008 Colon cancer Inhibit Inhibits the migration, invasion and EMT by inhibiting NF-κB signal transduction Cao B et al., 2013 Breast cancer Inhibit Inhibits cell proliferation and invasion, and weakens the growth and lung metastasis Gu X et al., 2012 Triple negative breast cancer Inhibit Inhibits tumor progress by changing the immune characteristics of tumor microenvironment, and it is mediated in a T cell-dependent manner Gibbs C et al., 2024 CXCL 15 CXCR2 N/A CXCL 16 CXCR6 SR-PSOX Lung cancer Promote Promotes the viability and invasion and leads to lung cancer metastasis Zhou W et al., 2011 Promotes proliferation and invasion by regulating NF-κB pathway Liang K et al., 2018 CXCL16-CXCR6 regulates lung cancer cell viability and invasion Hu W et al., 2014 Breast cancer Promote Blocking CXCR6-CXCL16/CXCR4-CXCL12 receptor-ligand interaction prevent brain metastasis Chung B et al., 2017 Prostate cancer Promote CXCL16/CXCR6 may be another independent axis of chemokines for bone metastasis Zhou W et al., 2010 Ovarian cancer Promote Maintains the high invasion and migration ability of cells by combining with CXCR6 Yang Y et al., 2015 Colon cancer Promote CXCL16/CXCR6 may be involved in the proliferation, invasion and metastasis Fu Y et al., 2017 Gastric cancer Promote Promotes tumorigenesis by enhancing ADAM10-dependent CXCL16/CXCR6 axis activation Han J et al., 2021 Promotes cell proliferation Takiguchi G et al., 2016 Promotes tumor progress through the expression of Ror1 mediated by STAT3 Ikeda T et al., 2020 Promotes tumorigenesis via ADAM10-dependent CXCL16/CXCR6 axis and activates Akt and MAPK signaling Han J et al., 2023 Adenocarci-noma Promote Enhances migration, invasion and adhesion with endothelial cells Singh R et al., 2016 Thyroid cancer Promote Enhances migration and invasion, and changes the phenotype of macrophages into M2 macrophages Zhao S et al., 2016 Breast cancer Inhibit Inhibits migration and invasion, and induces apoptosis of breast cancer cells Fang Y et al., 2014 Inhibits the migration and invasion of breast cancer cells in vitro Fang Y et al., 2013 Renal cancer Inhibit Inhibits migration of renal cell induced by CXCL16 Gutwein P et al., 2009 Colon cancer Inhibit CXCL16 can inhibit the metastasis of liver through NKT cells in CRC Kee J et al., 2013 Inhibits liver metastatic by promoting tumor-associated macrophage α TNF- induced apoptosis Kee J et al., 2014 CX3C CX3CR1 XCL1 XCR1 Breast cancer Promote Promotes the proliferation of drug-resistant cells by activating mTOR pathway Bai Y et al., 2015 The activation of ERK/HIF-1 α/EMT is involved in migration induced by XCL1 Do H et al., 2021 Inhibit Improves the survival rate by promoting cancer immunity Zhou W et al., 2020 XCL2 XCR1 Clear cell renal cell carcinoma Promote Inhibit apoptosis and promotes the proliferation, migration, invasion and epithelial-mesenchymal transition Cao Q et al., 2022 The role and mechanisms of chemokines in cancer Li Z et al., 2018 Iwata M et al., 2024 Xv Y et al., 2017 Wang M et al., 2022 CCR2 CCR4 CCR5 Yao M et al., 2017 Yao M et al., 2019 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cisplatin-induced apoptosis and supports the drug resistance Zhong Y et al., 2015 Li B et al., 2015 Li B et al., 2015 Zhang Z et al., 2016 Zhang Z et al., 2014 Johnson-Holiday C et al., 2011 Chen X et al.,2021 Sun A et al., 2022 LAN Q et al., 2018 CCR 10 Lin F et al., 2013 Yang X et al., 2017 Yan J et al., 2021 Facciabene A et al., 2012 Liu B et al., 2021 Huang G et al., 2016 Ren L et al., 2016 Zhou Y et al., 2013 Liu S et al., 2024 Park J et al., 2019 Cheng W et al., 2011 Wei Z et al., 2015 Wang Z et al., 2017 Xv T et al., 2018 Zhuo C et al., 2022 Xv T et al., 2018 Kong J et al., 2024 Ma K et al., 2018 Wang N et al., 2018 Zou A et al., 2023 Yang L et al., 2015 Cervix cancer Man X et al., 2022 Wei L et al., 2019 Zhang S et al., 2023 Miyake M et al., 2016 Zhang S et al., 2023 Park G et al., 2021 Ouh Y et al., 2018 Bolitho C et al., 2010 Zhang H et al., 2017 Lu Y et al., 2019 Yang X et al., 2023 Yang C et al., 2019 Han K et al., 2015 Benelli R et al., 2013 Liu C et al., 2020 Nie S et 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2024 CXCR1 CXCR2 Lin C et al., 2019 Ma J et al., 2015 Fang S et al., 2022 CXCR3 CXCR7 Tan S et al., 2018 Seitz S et al.,2022 CXCL 10 CXCR2 CXCR3 CXCR4 Wu X et al., 2020 Meng Q et al., 2022 Zhou H et al., 2016 Wang Z et al., 2021 Li A et al., 2024 Dong M et al., 2024 Li W et al., 2021 Zhang X et al., 2022 Jin W et al., 2017 Yan W et al., 2023 Yang L et al., 2012 CXCL 11 Liu G et al., 2022 Wang X et al., 2021 Liu M et al., 2021 Zeng YJ et al., 2016 Zeng X et al., 2022 Wang X et al., 2021 Xia J et al.,2011 Wang X et al., 2021 Hwang H et al., 2020 Furuya M et al., 2007 Furuya M et al., 2011 Lo B et al., 2010 Liang J et al., 2021 Fallahi P et al., 2018 Gao Y et al., 2018 Sun L et al., 2019 Harlin H et al., 2009 Gacci M et al., 2009 Zhang C et al., 2018 Pasini F et al., 2014 Mitsuhashi A et al., 2021 Zhang Y et al., 2019 CXCL 12 CXCR4 CXCR7 Imai H et al., 2010 Ma J et al., 2014 Silencing CXCL12 inhibits proliferation, invasion and angiogenesis by down-regulating MAPK/PI3K/AP-1 signaling Ma J et al., 2018 Shen B et al., 2014 Lei P et al., 2015 Prostate cancer Zhang S et al., 2009 Wald O et al., 2011 Ma J et al., 2017 Song Z et al., 2015 Wang M et al., 2018 Zhang Z et al., 2023 Phillips R et al., 2003 Xin Q et al., 2016 Zhang F et al., 2020 Wu Y et al., 2012 Luo N et al., 2020 Yadav S et al., 2016 CXCL 13 CXCR4 CXCR7 Geng S et al., 2020 Zhao C et al., 2021 Qi X et al., 2013 Zhu Z et al., 2015 Zhao Q et al., 2021 Tian Q et al., 2019 Zheng Z et al., 2019 Liu J et al., 2020 Xv L et al., 2018 Ma Q et al., 2021 Ma D et al., 2020 CXCL 14 CXCR4 CXCR7 Zhang Z et al., 2023 Li X et al., 2021 Wente M et al., 2008 Cao B et al., 2013 Gu X et al., 2012 Gibbs C et al., 2024 CXCL 15 CXCL 16 CXCR6 SR-PSOX Zhou W et al., 2011 Liang K et al., 2018 Hu W et al., 2014 Chung B et al., 2017 Zhou W et al., 2010 Yang Y et al., 2015 Fu Y et al., 2017 Han J et al., 2021 Ikeda T et al., 2020 Han J et al., 2023 Singh R et al., 2016 Zhao S et al., 2016 Fang Y et al., 2014 Fang Y et al., 2013 Kee J et al., 2013 Kee J et al., 2014 Bai Y et al., 2015 Do H et al., 2021 Zhou W et al., 2020 Cao Q et al., 2022 As the innate immune system receptors and sensors, inflammasomes are multiprotein complexes, which react to recognized indicators of endogenous (linked to cellular damage, ATP, ROS, and DNA) and external (related to infections) stimuli [ 302 ]. Inflammasome components include the NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD) domain-containing protein 1 (NLRP1), nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain-containing receptor (NLRP3)( (also known as cryopyrin), NLR family caspase activation and recruitment domain-containing protein 4 (NLRC4), NOD-like receptor family pyrin domain containing 6 (NLRP6), and absent in melanoma 2 (AIM2). Detailed information on the structure of NLRP1, NLRP3, NLRP4, NLRP6, and AIM2 are shown in Fig. 4 . Their products like interleukin 1β and interleukin 18, along with the adaptor, apoptosis-associated speck-like protein containing caspase activation and recruitment domain (ASC) and the effector caspase-1 both play a major role in carcinogenesis [ 303 ]. The sensor protein on each type of inflammasome determines whether a form of the inflammasome is present by identifying pathogenic ligands and triggering the assembly of inflammasomes. NLRs convert the biologically inactive pro-IL-1beta and pro-IL-18 into their active forms through caspase-1 [ 304 ]. Genetic mutations in NLRP1, NLRP3, NLRC4, and AIM2 are linked with the development of auto-inflammatory diseases, enterocolitis, and cancer [ 305 ]. It is commonly known that inflammatory proteins and their byproducts have a role in developing several cancers, such as skin cancer [ 306 ], lung cancer [ 307 ], and others. Inflammasomes play both protective and detrimental roles in cancer. On one hand, mice that lack NLRP3, ASC, or caspase-1 exhibit increased susceptibility to colitis and to colitis-associated colorectal cancer induced by the chemical colitogen dextran sulfate sodium (DSS) [ 308 , 309 ]. Infusion of recombinant IL-18 reduces tumor frequency in mice deficient in inflammatory components following azoxymethane (AOM) and DSS treatment [ 308 ]. IL-18 plays a role in repairing the epithelial barrier and preventing damage [ 309 ]. This may clarify the protective roles of NLRP3 and IL-18 in relation to colitis-associated colorectal cancer. Mice that lack IL-18 are more vulnerable to developing lung metastasis [ 310 ]. Mice that were injected daily with recombinant IL-18 for five days exhibited fewer lung metastases [ 311 ]. Other NLR sensors, such as NLRP6 and NLRP1b, have also shown protective effects against tumorigenesis. For instance, the NLRP1b inflammasome mediates the secretion of IL-1β and IL-18 in stromal colon cells, providing protection against colon tumorigenesis [ 312 ]. NLRP6 protects against chemical-induced colon cancer by activating caspase-1 and promoting IL-18 production in the intestine [ 313 ]. The blockade of ASC promotes the growth of melanoma tumors [ 314 ]. On the other hand, In some cases, the activation of the inflammasome can suppress antitumor immunity. For instance, when B16-F10 melanoma cells or RM-1 prostate cancer cells are delivered intravenously (as opposed to subcutaneously) into mice, the activation of NLRP3 is associated with increased lung metastasis. The harmful impact of NLRP3 in melanoma may stem from its inhibitory effect on the activation of NK cells, which are responsible for secreting IFNγ and killing tumor cells.In some cases, inflammasome activation can suppress antitumor immunity. For example, when B16-F10 melanoma or RM-1 prostate cancer cells are delivered intravenously into mice, NLRP3 activation is linked to increased lung metastasis. This detrimental effect may be due to NLRP3’s inhibition of NK cell activation, which is crucial for secreting IFNγ and killing tumor cells [ 310 ]. Recombinant IL-18 increases lung metastasis when injected into mice twice a week [ 311 ]. The knockdown of the gene encoding ASC suppresses the growth of melanoma xenograft tumors [ 314 ]. The types of cells, tissues, and organs involved in an inflammasome significantly influence its characteristics related to tumor promotion and suppression. The biological link between inflammasomes and cancer offers promising opportunities for exploring novel anticancer therapies. Fig. 4 Nucleotide-binding domain, leucine-rich repeat containing receptors (NLRs) upon activation form a multiprotein complex known as the “inflammasome”. The inflammasome complex consists of an NLR protein, the apoptosis-associated speck-like protein (ASC) (an adaptor protein) and a caspase. The detailed information on the structure of NLRP1, NLRP3, NLRP4, NLRP6, and AIM2 inflammasome are shown. A NLRP1 consists of both pyrin domian (PYD) and caspase recruitment domain (CARD) along with the function to find domain (FIIND domain). NLRP1 directly recuits procaspase-1 through its CARD domain. B The Nlrp3 gene encodes an N-terminal PYD domain, a central nucleotide binding and oligomerization domain (NBD) and a C-terminal leucine-rich repeats (LRR). NLPR3 lacks a CARD domain and therefore, interacts with ASC to recruit procaspase-1. C The Nlrp6 gene encodes an N-terminal PYD domain, a central NBD domain and a C-terminal LRR. NLRP6 is recruited to the “specks” formed by ASC oligomerization, leading to procaspase-1 activation. D The Nlrc4 gene encodes an N-terminal CARD domain, a central NBD domain, and C-terminal LRR. The interaction of NLRC4 with ASC is unclear. NLRC4 results in pro-IL-1b and proIL-18 processing or caspase-1-dependent pyroptosis via an ASC-dependent mechanism or an ASCindependent mechanism. E The AIM protein consists of a N-terminal PYD domain, mediating homotypic interactions with ASC and a C-terminal HIN-200 domain for DNA binding Nucleotide-binding domain, leucine-rich repeat containing receptors (NLRs) upon activation form a multiprotein complex known as the “inflammasome”. The inflammasome complex consists of an NLR protein, the apoptosis-associated speck-like protein (ASC) (an adaptor protein) and a caspase. The detailed information on the structure of NLRP1, NLRP3, NLRP4, NLRP6, and AIM2 inflammasome are shown. A NLRP1 consists of both pyrin domian (PYD) and caspase recruitment domain (CARD) along with the function to find domain (FIIND domain). NLRP1 directly recuits procaspase-1 through its CARD domain. B The Nlrp3 gene encodes an N-terminal PYD domain, a central nucleotide binding and oligomerization domain (NBD) and a C-terminal leucine-rich repeats (LRR). NLPR3 lacks a CARD domain and therefore, interacts with ASC to recruit procaspase-1. C The Nlrp6 gene encodes an N-terminal PYD domain, a central NBD domain and a C-terminal LRR. NLRP6 is recruited to the “specks” formed by ASC oligomerization, leading to procaspase-1 activation. D The Nlrc4 gene encodes an N-terminal CARD domain, a central NBD domain, and C-terminal LRR. The interaction of NLRC4 with ASC is unclear. NLRC4 results in pro-IL-1b and proIL-18 processing or caspase-1-dependent pyroptosis via an ASC-dependent mechanism or an ASCindependent mechanism. E The AIM protein consists of a N-terminal PYD domain, mediating homotypic interactions with ASC and a C-terminal HIN-200 domain for DNA binding Besides, other studies also point to the tumor-suppressive function of inflammasomes like NLRP3, NLRP1, NLRP6, and Pyrin in the initiation and spread of some malignancies, including colorectal cancer [ 315 ]. Recently, some inhibitors and agonists of these inflammasomes exhibit anti-tumor effects. For example, the small molecule OLT1177 suppressed tumor growth by inhibiting NLRP3 [ 316 ]. OLT1177 and another NLRP3 inhibitor MCC950 reduced tumor growth in melanoma [ 317 , 318 ]. Nigericin controls tumor growth by activating NLRP3 in breast cancer and neuroblastoma [ 319 ]. Since the multifaceted role of inflammasomes in carcinogenesis, clarifying the mechanism of action in different tumors will provide novel therapeutic approaches for cancer treatment and prevention. Here, we will summarize the promoting and suppressive effects of these inflammasomes and their inhibitors and agonists in cancer initiation and development. A comprehensive list of the role of these inflammasomes in cancer is also shown in Table 7 . Table 7 The role and mechanisms of inflammasome in cancer Inflammasome Cancer types Promote/inhibit Mechanisms References NLRP1 Breast cancer Promote Promotes tumorigenesis and proliferation Wei, Y et al.,2017 Prostate cancer Promote Enhances tumorigenesis by promoting the maturation and release of pro-inflammatory cytokines IL-1β Liang, K et al.,2023 Metastatic melanoma Promote Enhances inflammasome activation and suppresses apoptosis Zhai, Z et al.,2017 High p62 (NLRP1 inhibitor) Cutaneous SCC cells Promote Suppresses the NLRP1 inflammasome and increases stress resistance Hennig, P et al.,2022 Non-melanoma skin cancer Promote Lower NLRP1 level is associated with worse clinical outcomes and poorer prognosis Tan, J et al.,2023 Triple-negative breast cancer Inhibit Contribute to the antiproliferative effects of celecoxib Arzuk, E et al.,2024 NLRP3 Colorectal cancer Promote Contributes to cell migration and invasion Deng, Q et al.,2019 Promotes invasion and migration Zhang, L et al.,2022 Ovarian cancer Promote Contributes to the malignant process of DDP-resistant cells Li, W et al.,2023 3,4-Methylenedioxy-β-nitrostyrene (MNS) (NLRP3 inhibitor) Pancreatic ductal adenocarcinoma Inhibit Inhibits inflammation and restores immunity Liu, H et al.,2020 MCC950 (NLRP3 inhibitor) Pancreatic ductal adenocarcinoma Inhibit Inhibits LPS-induced pancreatic adenocarcinoma inflammation Yaw, A et al.,2020 Vitamin D (NLRP3 inhibitor) Breast cancer Inhibit Mediates the modulation of stemness Zheng, W et al.,2024 Caffeic Acid Phenethyl Ester (NLRP3 inhibitor) Colon cancer Inhibit Inhibits NLRP3 Inflammasome Dai, G et al.,2020 RNF20 (NLRP3 inhibitor) Liver cancer Inhibit Reduces cell proliferation and Warburg effect by promoting NLRP3 ubiquitination Liu, D et al.,2024 Metformin (NLRP3 inhibitor) Colorectal cancer Inhibit Delays tumor progression Liu, G et al.,2024 Fermented Quercetin (NLRP3 inhibitor) Colorectal cancer Inhibit Decreases resistin-induced chemo-resistance to 5-Fluorouracil Lee, K et al.,2022 Inhibition of HDAC2 (NLRP3 agonist) Breast cancer Inhibit Sensitizes anti-tumour therapy by promoting NLRP3/GSDMD- mediated pyroptosis Guan, X et al.,2024 H. pylori CagA (NLRP3 agonist) Gastric cancer Promote Promotes invasion and migration by activating NLRP3 inflammasome pathway Zhang, X et al.,2021 Cervical cancer Promote Promotes migration, invasion and EMT by regulating macrophage differentiation Zhou, H et al.,2020 miR-223-3p (NLRP3 inhibitor) Prostate cancer Inhibit Reduces tumor growth and immunosuppression Zhang, L et al.,2019 miR-22 (NLRP3 agonist) Prostate cancer Inhibit Inhibits PI3K/AKT signaling pathway Wu, H et al.,2021 NLRC4 Glioma Promote Contributes to a poor prognosis Lim, J et al.,2019 Lung adenocarcinoma Cells Promote Induces apoptosis and immune infiltration Hu, B et al.,2023 Melanoma tumor Promote Suppresses tumor growth in an inflammasome-independent manner Janowski, A et al.,2016 Breast cancer Inhibit Weakens the ability of flagellin to inhibit tumor proliferation Zhang, J et al.,2019 NLRP6 Colorectal cancer Promote Promotes liver metastasis by modulating M-MDSC-induced immunosuppressive microenvironment Chang, L et al.,2024 Gastric cancer Inhibit Suppresses tumorigenicity Wang, Q et al.,2018 Suppresses tumor growth via GRP78 ubiquitination Wang, X et al.,2020 Mediates P14ARF-Mdm2-P53-dependent cellular senescence Wang, H et al.,2018 AIM2 Prostate cancer Promote IFN-inducible AIM2 protein is a cytosolic DNA sensor in macrophages and keratinocytes Ponomareva, L et al.,2013 Colon cancer Inhibit Suppresses colon tumorigenesis via DNA-PK and AKT Wilson, J et al.,2015 Bladder cancer Inhibit Inhibits tumorigenesis and enhances the therapeutic effect Zhou, H et al.,2022 Colorectal cancer Inhibit Inhibits cell proliferation and migration through suppressing Gli1 Xu, M et al.,2020 The role and mechanisms of inflammasome in cancer Wei, Y et al.,2017 Liang, K et al.,2023 Zhai, Z et al.,2017 Hennig, P et al.,2022 Tan, J et al.,2023 Arzuk, E et al.,2024 Deng, Q et al.,2019 Zhang, L et al.,2022 Li, W et al.,2023 Liu, H et al.,2020 Yaw, A et al.,2020 Dai, G et al.,2020 Liu, D et al.,2024 Liu, G et al.,2024 Lee, K et al.,2022 Guan, X et al.,2024 Zhang, X et al.,2021 Zhou, H et al.,2020 Zhang, L et al.,2019 Wu, H et al.,2021 Lim, J et al.,2019 Hu, B et al.,2023 Zhang, J et al.,2019 Chang, L et al.,2024 Wang, Q et al.,2018 Wang, X et al.,2020 Wang, H et al.,2018 Ponomareva, L et al.,2013 Wilson, J et al.,2015 Zhou, H et al.,2022 Xu, M et al.,2020 The receptor NLRP1, the adaptor protein ASC, and the effector protein caspase-1 make up the multi-protein complex known as the NLRP1 inflammasome. NLRP1 is the first identified and currently recognized predominant inflammasome sensor protein in human keratinocytes, NLRP1 has its unique domain, which contains an effector C-terminal caspase recruitment domain (CARD), PYD, a central NBD, an LRP and a function to find domain (FIIND). In the absence of external stimuli, the NBD binds to LRR, inhibiting self-oligomerization and bringing the protein into an inactive state. When cells are exposed to external stimuli, such as viruses, UVB rays, and ribotoxic stress reactions, they bind to the LRR domain, then induce a conformational change in NLRP1 and expose PYD and CARD domains. The downstream proteins which containing PYD and CARD are then mediated, such as the homologous interaction between ASC and caspase-1. Dipeptidyl protease (DPP), anthrax lethal toxin (LT), and parasites can activate NLRP1 [ 320 ]. Database analysis indicates that NLRP1 has a distinct expression pattern across various tumors, and patients with high NLRP1 expression generally have a better prognosis in lung adenocarcinoma (LUAD) and pancreatic adenocarcinoma (PAAD) [ 321 ]. The activation of the NLRP1 sensor protects against colitis-associated CRC through mechanisms dependent on effector cytokines [ 315 ]. NLRP1 is also positively correlated with an increased risk of prostate cancer [ 322 ]. The dysfunctions in the NLRP1 pathway are also linked to skin cancers, including melanoma, Kaposi sarcoma, and squamous cell carcinoma [ 323 ]. Increased expression of NLRP1 was significantly associated with immune cell infiltration in gastric cancer [ 324 ]. An endogenous thioredoxin (TRX) has been identified as a binder to NLRP1 and inhibits NLRP1 inflammasome activation. This opens opportunities for therapeutic intervention in NLRP1 inflammasome activation in the future. The NLRP3 inflammasome is widely present in immune cells. As the most thoroughly studied inflammasome, NLRP3 inflammasome includes the sensor NLRP3, the adaptor ASC, and the effector caspase-1. NLRP3 consists of three domains, a central nucleotide-binding domain (NBD), a C-terminal leucine-rich repeat (LRR), and an N-terminal PYD. ROS production, ionic flux, mitochondrial dysfunction, and lysosomal damage are the four main activation mechanisms of NLRP3 inflammasome. Under the stimulation of microbial or endogenous molecules like TLR ligands, NF-κB is activated, and pro-IL-1β, pro-IL-18, and NLRP3 are induced. Then, various stimuli like extracellular ATP, glucose, bacterial and virus infection, mitochondrial damage/dysfunction, and more facilitated the maturation of pro-IL-1β and pro-IL-18, promoting the activation of NLRP3 inflammasome. NLRP3 and NLRP3 inflammasome members like caspase-1, IL-1β and IL-18 are potential therapeutic targets due to their role in inflammation-associated diseases and cancer. Recent research reported that NLRP3 inflammasome-related genes were dysregulated in 15 cancers [ 325 ]. NLRP3 is overexpressed and activated in several cancers, like non-small cell lung cancer [ 326 ], melanoma [ 327 ], and more. Patients with cancer have a higher frequency of Nlrp3 polymorphism, such as pancreatic cancer [ 328 ], melanoma [ 329 ], and others. They were introduced as a double-edged sword in tumorigenesis. On one hand, the NLRP3 inflammasome promotes tumor formation and metastasis in breast cancer [ 330 ], and overexpressed human IL-1β in mice stomach increases the risk of gastric cancer [ 331 ]. NLRP3 affects the adaptive immune system to promote carcinogenesis in pancreatic cancer [ 332 ], and pharmacologic blocking of NLRP3 enhances the efficacy of immunotherapy [ 318 ]. NLRP3 signaling promotes T cell differentiation into tumor-promoting T cell populations and restricts antitumor T cell immunity [ 333 ]. NLRP3-mediated IL-1β production promotes pancreatic ductal adenocarcinoma by immunosuppression [ 334 ]. On the other hand, mice deficient in NLRP3 are hypersusceptible to carcinogen-induced colitis-associated cancer (CAC) [ 335 ]. While NLRP3 inhibition via mitophagy prevents CAC, indicating a harmful role of NLRP3 in CAC [ 336 ]. The differences in gut microbiota, genetic background, and experimental technique may explain the inconsistent effects of NLRP3 in CAC. Besides, NLRP3 is down-regulated in hepatic cancer tissues [ 337 ], and the up-regulation of NLRP3 inhibits hepatic cancer cell growth [ 338 ]. The varying functions of NLRP3 in the etiology of cancer present novel prospects and obstacles in comprehending its dual roles of pro- and anti-tumorigenic effects. The tumor microenvironment may have an impact on these many functions by altering NLRP3 activity. Furthermore, it appears that NLRP3 plays distinct roles in the pathophysiology of cancers that originate in particular organs due to its variable expression in different cells and tissues, and elucidating the role and mechanism of NLRP3 in different cancers will contribute to precision therapy. NLRC4 contains three domains: the N-terminal CARD domain, the C-terminal LRR domain, and the NACHT domain. NACHT domain is composed of the NBD, helical domain 1 (HD1), winged helix domain (WHD), and helical domain 2 (HD2). A functional type IV secretion system (T4SS) for L. pneumophila or a functional type III secretion system (T3SS) for S. Typhimurium, S. flexneri, and P. aeruginosa is necessary for NLRC4 inflammasome activation [ 339 ]. Regulatory mechanisms also impact NLRC4 activation, mostly comprising transcription control and post-translation changes, specifically phosphorylation and perhaps ubiquitination. Interferon regulatory factor (IRF) 8 induces NLRC4 transcription, and infection with S. typhimurium induces NLRC4 phosphorylation at serine 533 [ 340 ]. Flagellin also induces NLRC4 phosphorylation but can’t activate NLRC4 inflammasome [ 341 ]. NLRC4 has been shown to express differently yet variably across various tumor tissues. For example, NLRC4 mRNA level is increased in stomach cancer, glioma, and breast cancer, but it is decreased in colorectal cancer compared with normal adjacent tissues [ 339 ]. However, NLRC4 mRNA is almost unchanged in hepatocellular carcinoma [ 342 ]. And there is no agreement regarding its role in any form of cancer development, even in the same tumor type. Knocking out NLRC4 promotes tumor formation in colon cancer [ 343 ] and melanoma [ 344 ]. Higher NLRC4 expression is closely related to poor prognosis in breast cancer [ 345 ] and glioma [ 346 ]. Activated NLRC4 inflammasome activates IL-1β, which promotes breast cancer progression by adipocyte-mediated vascular endothelial growth factor A (VEGFA) expression and angiogenesis [ 345 ]. Besides, in colitis-associated tumorigenesis, the role of NLRC4 depends on how NAIPs function. NAIPs have protective effects on colon cancer development, which is independent of NLRC4 [ 347 ]. Even though there isn’t a consensus on the involvement of NLRC4 or NAIP in cancer, the necessity to employ littermate controls in these experiments will improve future research consistency and reproducibility. Furthermore, the discovery of NAIPs’ or NLRC4’s inflammasome-independent activities in carcinogenesis is intriguing because it might reveal new route targets for the creation of immunotherapies. As a recently identified receptor in the mammalian innate immune system, the NOD-like receptor family pyrin domain containing 6 (NLRP6) was formerly known as PYPAF5 [ 348 ]. It comprises N-terminal PYD, central NBD, and C-terminal LRR domain. Following the recognition of PAMP and DAMP, NLRP6 forms the NLRP6 inflammasome by assembling with ASC and Caspase-1. This process facilitates the maturation of pro-IL-1β and pro-IL-18, as well as gasdermin-D-induced pyroptosis. NLRP6 functions as an inflammasome or a non-inflammasome in a variety of ways. Various factors can regulate the activation of NLRP6. For example, mouse macrophages bind to lipoteichoic acid and stimulate the assembly of the NLRP6 inflammasome [ 349 ]; microbial signals of type I IFN and PPAR-γ agonists regulate NLRP6 transcription [ 350 , 351 ]; microbial metabolites activate or inhibit the NLRP6 inflammasome [ 352 ]. NLRP6 gene-deficient mice got more colitis-associated colorectal tumors after AOM/DSS treatment [ 313 ]. Elinav’s experiment suggests that the main source of active IL-18 generation through NLRP6 may be intestinal epithelial cells [ 353 ], which explains that NLRP6 gene-deficient animals’ serum and colon tissue showed decreasing levels of IL-18 with time but not IL-1. NLRP6 also plays a critical regulatory role in the linked pathogenic changes before HCC. For example, NLRP6 inflammasome and effector protein IL-18 suppress the development of NAFLD/nonalcoholic steatohepatitis (NASH) and metabolic syndrome by regulating intestinal microbiota [ 354 ]. NLRP6 overexpression reduces steatosis, inflammation, and fibrosis and lowers the production of CCL20 in alcoholic hepatitis (AH) animal models [ 355 ]. On the contrary, inhibiting the activation of NLRP6 inflammasome may improve liver steatosis in mice [ 356 ]. The contradictory conclusions regarding the role of NLRP6 in HCC may be due to the different stages of the disease and the differences in experimental models and methods. Further studies are needed to define the role of NLRP6 in the development and spread of HCC and comprehend the extent to which NLRP6 switches from inhibiting tumor growth to promoting malignancy. Besides, NLRP6 functions as a tumor suppressor factor in gastric cancer (GC) [ 357 ] while promoting small cell lung cancer (SCLC) metastasis [ 307 ]. Even though there is low or no expression of NLRP6 in other organs except for the colon, liver, and stomach, it’s also related to other organ diseases such as brain injury [ 358 ] and acute renal injury [ 359 ]. These suggest the potential role of NLRP6 in the carcinogenesis of these organs, and further studies are needed to expand the cognitive boundaries of NLRP6 research. As the best-characterized member of the AIM2-like receptors (ALRs), AIM2 contains the N-terminal PYD domain and one or two C-terminal HIN domains (hematopoietic, interferon-inducible, and nuclear localization). The multicomponent AIM2 inflammasome is formed when AIM2 recognizes dsDNA and recruits the adaptor protein ASC, which then activates caspase-1 [ 360 ]. AIM2 can be directly activated by transfection of dsDNA into the cytoplasm [ 361 ] and DNA derived from the gut microbiota or host-DNA released after intestinal injury [ 362 ]. While AIM2 activation is negatively regulated by several factors such as IFI16-β [ 363 ], IFN-inducible protein PYD-only protein 3 (POP3) [ 364 ], and the viral protein pUL83 released during human cytomegalovirus (HCMV) [ 365 ], herpes simplex virus-1 (HSV-1) tegument protein VP22 [ 366 ], hepatitis B e-antigen (HBeAg) [ 367 ], HCMV IE86 protein [ 368 ] and others. Besides, ubiquitinated TRIM11 promotes p62-dependent selective autophagy-induced AIM2 inflammasome degradation following DNA stimulation [ 369 ]. AIM2 has bidirectional roles in tumorigenesis in different types of cancer. In hepatic and colon cancer, AIM2 suppresses tumor growth [ 370 ], whereas in cutaneous squamous cell carcinoma, it promotes tumor growth [ 371 ]. AIM2 contains a site for microsatellite instability, which leads to gene mutations in CRC and inhibits its development [ 372 , 373 ]. Additionally, it was demonstrated that AIM2 has a role in the pathophysiology of DNA damage caused by chemotherapy, suggesting that medications targeting AIM2 may offer therapeutic advantages during radiation therapy [ 362 ]. These indicate that suppressing the activity of AIM2 inflammasome could be investigated due to their role in carcinogenesis. During the past decade, several synthetic inhibitors of AIM2 such as suppressive oligodeoxynucleotides [ 364 ], pyrin-containing proteins, and antimicrobial cathelicidin peptides [ 374 ] have been discovered, and exploring their anti-tumor effect and underlying mechanisms are promising strategies for cancer prevention and treatment. In human leukemia cells treated with chemotherapeutics drugs, ASC was first identified as a protein that aggregates (or “specks”), which was also known as PYCARD/Target of Methylation-induced Silencing-1 (TMS1). The ASC/TMS1 protein has a 22 kDa structure and comprises two domains: the C-terminal CARD domain and PYD domain [ 375 ]. Several immune and normal epithelial cells express ASC/TMS1, which localizes in the nucleus, redistributes in the cytoplasm during activation, and finally aggregates into specks [ 376 ]. ASC can be either increased in tumor cells and overexpressed in the myeloid compartment (mostly TAMs) within the tumor microenvironment, or downregulated in malignancies, primarily due to aberrant methylation. On one hand, it is a key adapter molecule of the inflammasome complex, which is responsible for mediating the release of inflammatory cytokines of IL-1β and IL-18, which were known to have tumor-promoting effects [ 377 – 379 ]. Besides, ASC also exhibits pro-tumor effects through other indirect pathways such as chronic inflammation, macrophage recruitment, IL-17 pathway activation, angiogenesis, and others [ 378 ]. On the other hand, ASC was downregulated in several types of cancer, and the tumor-suppressive effect of ASC was supported by the discovery that methylation silences its expression and prevents tumor cells from passing through apoptosis [ 380 ]. Besides, the regulatory effect of ASC on thymic stromal lymphopoietin (TSLP) secretion by cancer-associated fibroblasts (CAFs) contributes to improving the overall survival of pancreatic cancer patients [ 381 ]. ASC delays UV-induced skin tumorigenesis [ 382 ]. ASC inhibits lung cancer suppression via Bcl-2 and pSrc [ 383 ]. Restoring ASC expression makes colorectal cancer cells more susceptible to caspase-independent cell death caused by genotoxic stress [ 380 ]. In addition, ASC showed dual roles even in the same type of tumor. For example, ASC inhibits tumorigenesis in primary melanoma, while ASC promotes tumorigenesis in metastatic melanoma [ 314 ]; mice had fewer tumors when ASC was specifically deficient in myeloid cells, while mice had more tumors when ASC was specifically deficient in keratinocyte cells [ 384 ]. These opposing functions of ASC may be due to the tissue or cell-specific expression context, and dissecting the role of ASC in different cancer types and additional research on ASC and its upstream and downstream mediators may improve our comprehensive of molecular processes behind carcinogenesis and contribute to the ASC targeting strategies for cancer treatment and prevention. As a highly dynamic structure, the extracellular matrix (ECM) is present in all tissues and constantly undergoing controlled remodeling. ECM comprises large, insoluble proteins mainly formed of separate structural domains with highly conserved sequences and arrangements. These domains are glycosylated and often have sulfated glycosaminoglycan chains, resulting in negative charges [ 385 ]. This characteristic of ECM molecules gives them great potential to interact with other charged molecules, like growth factors and chemokines, to affect the accessibility or local concentration of these factors [ 386 ]. Since collagen, the most abundant ECM component, was first identified and characterized in the 1930s. In chronically inflamed tissues, the ECM fragments or ECM molecules are upregulated, and they’re modulated by proteases, especially MMPs, and inflammatory cytokines such as TNF, IFNγ, and TGFβ generated by extravasating cells or activated tissue-resident cells. Recent research has found that immune cells can be stimulated by ECM components or fragments that are increased during inflammation, thus sustaining the inflammatory response. On the one hand, ECM can serve a structural role as a barrier or scaffold for cells that invade inflamed tissues. On the other hand, the biophysical characteristics and their biochemical makeup provide immune cells with specific signals that regulate proliferation, migration, apoptosis, adhesion, differentiation, and survival. Aberrant ECM influences immune cell behavior, such as infiltration and activation, and plays a role in cancer metastasis. For example, activating the collagen receptor DDR1 can enhance macrophage infiltration in atherosclerotic plaques [ 387 ]. The size and density of collagen fibrils can influence the migration of immune cells [ 388 ]. Although immune cell infiltration is promoted, collagen type I hinders macrophages from effectively killing cancer cells by blocking their polarization and subsequent activation [ 389 ]. This highlights the complex characteristics of how ECM deregulation modulates the immune response. Furthermore, breast cancer cells with high levels of the hyaluronan receptor CD44 have a better survival rate compared to those with low CD44 levels [ 390 ]. This indicates that hyaluronan and possibly other components of the extracellular matrix support the survival of metastatic cancer cells. Tenascin-C (TNC) is a glycoprotein that plays a significant role in the ECM and is notably expressed in pathological conditions, particularly in cancer and chronic inflammatory diseases. TNC activates TLR4, which in turn stimulates macrophages and fibroblasts to release pro-inflammatory cytokines such as IL-6, IL-8, and TNF-α [ 391 ], and affects the recruitment of immune cells [ 392 ]. Higher TNC expression was observed in melanoma cells from advanced tumors and metastases, while early melanoma tumors and normal melanocytes displayed weak or absent TNC expression [ 393 ]. Tenascin-C is located in the bone endosteum and contributes to the development of prostate bone metastases [ 394 ]. TNC deficiency in human breast cancer cells significantly decreases metastasis to the lungs and bones in xenograft models [ 395 ]. Dysregulated ECM remodeling leads to many diseases, including cancer. As one of the major components of cancer, the ECM plays various crucial roles in signaling regulation, microenvironment modulation, and mechanical support. The ECM shows multifaceted effects in regulating multiple hallmarks, including angiogenesis, tumor progression, immune response, and cancer cell migration of cancer. Under specific circumstances, the ECM restrains malignant tumor progression [ 396 ]. However, the ECM also promotes tumor progression [ 389 ]. Collagen IV over-expression boosts cell survival of lung cancer [ 397 ]. The ECM also facilitates the metastasis of cancer cells [ 398 ]. The miR-29 over-expression inhibits metastasis by regulating gene expression in ECM remodeling in breast cancer [ 399 ]. This suggests that blocking the ECM molecules may be therapeutically beneficial for cancer prevention and treatment. The ECM components including tenascin C, endostatin, tumstatin, canstatin, arresten, and hexastatin also have pro- and anti-angiogenic functions. For example, tenascin C promotes cancer cell proliferation and induces angiogenesis [ 400 ]. Arresten suppresses the angiogenesis of HUVECs by blocking PI3K/Akt signaling pathway [ 401 ]. The ECM plays a vital role in regulating immune responses. For example, the ECM niche in the spleen promotes the differentiation and survival of marginal zone B cells to support antibody production [ 402 ]. Besides, matrikines regulate immune cell behaviors such as the interaction of immune cells with cancer cells [ 403 ], the recruitment and activation of immune cells [ 404 ], and more. Here, we will summarize the role of the ECM components including ECM proteins, ECM fragments, the proteases that cleave the ECM, the MMPs that degrade the ECM, and others, the underlying mechanisms are also illustrated. A deeper comprehension of the biological activities of the ECM will provide intriguing opportunities for therapeutic intervention of cancer. More details regarding the function of ECM proteins and fragments in cancer are provided in Table 8 . Table 8 The role and mechanisms of extracellular matrix (ECM) and related proteins in cancer ECM proteins Cancer types Promote/inhibit Mechanisms References Collagen Non-small cell lung cancer Promote Regulates overall survival and cell differentiation Fang, S et al., 2019 Lung cancer Promote Collagen XXIII is highly expressed in lung cancer Spivey, K et al., 2010 Esophageal squamous cell carcinoma Promote Regulates overall survival and cell differentiation Fang, S et al., 2019 Drives invasion through a YAP-centered transduction loop Khalil, A et al., 2024 Breast cancer Promote Promotes tumor progression and metastasis Xiong, G et al., 2014 Hepatocellular carcinoma Promote Promotes cell proliferation, adhesion, invasion, metastasis and angiogenesis Zhang, J et al., 2022 Lung cancer Promote Promotes metastasis, invasion and anoikis resistance Zhang, H et al., 2018; Promotes cell growth in a three- dimensional culture system Li, J et al., 2014 Pancreatic cancer Promote Stimulates proliferation, migration, and inhibits apoptosis via autocrine loop Ohlund, D et al., 2013; Promotes the malignant phenotype of pancreatic cancer cells Armstrong, T et al., 2004 Promotes metastasis by activating c-Jun NH2-terminal kinase 1 and up-regulating N-cadherin expression Shintani, Y et al., 2006 Prostate cancer Promote Lactate supports ECM production to sustain metastatic behavior Ippolito, L et al., 2024 Correlates with recurrence and distant metastasis Banyard, J et al., 2007 Head and neck squa mous cell carcinoma Promote Promotes cancer cell invasion Chen, Yin-Q et al., 2019 Ovarian cancer Promote Influences proliferation Sarwar, M et al., 2022 Increases proliferation Fogg, K et al., 2020 Liver cancer Promote Promotes inflammatory response and proliferation Shen, X et al., 2024 Gastric cancer Promote Promotes fibroblast collagen synthesis NAITO, Y et al., 1984 Squamous cell carcinoma, prostate cancer, colorectal cancer, lung cancer Promote Collagen remodeling along cancer progression and provides a novel opportunity for cancer diagnosis and treatment Song, K et al., 2022 Non-small cell lung cancer Inhibit Inhibits CAF-mediated collagen remodeling, cell migration and invasion Zeltz, C et al., 2022 Colorectal cancer Inhibit Inhibits cell differentiation and promotes a stem cell-like phenotype Kirkland, S et al., 2009 Breast cancer Inhibit Regulates adhesion and migration after the collagen is mineralized Choi, S et al., 2019 Proteoglycans Brain cancer Promote Modulates migration, cell adhesion, tumor invasion, and neurite outgrowth Yan, Z et al., 2020 Promotes receptor tyrosine kinase signaling and progression Wade, A et al., 2013 Liver cancer Promote Interacts with many growth factors and relates to tumor invasion Baghy, K et al., 2016 Breast cancer Promote Restores FGF-2 mitogenic activity Delehedde, M et al., 1996 Esophageal squamous cell carcinoma Promote Regulates cell survival, invasion and metastasis Li J et al., 2019 Pancreatic cancer Promote Stimulates cell growth Zvibel, I et al., 2001 testican-1 Colorectal cancer Promote Promotes cell proliferation and invasion through PI3K/AKT pathway Zhao P et.al, 2016 testican-1 Gastric cancer Promote Induces EMT Kim HP et.al, 2014 lumican Pancreatic cancer Inhibit High expression correlates with favorable survival after surgery Li X et.al, 2014 Breast, hepatocellular, lung and prostate cancer , melanoma and multiple myeloma Inhibit Inhibits heparanase and growth factor-growth factor receptor active complex formation, sequestrates growth factors in ECM, inhibits cell proliferation, metastasis and angiogenesis Koo, C et al., 2008 syndecan-1, endostatin, decorin Esophageal squamous cell carcinoma Inhibit Regulates cell survival, invasion,metastasis and angiogenesis Ji C et.al, 2015 Glycoproteins Colorectal cancer Promote Decreases the sensitivity of doxorubicin Hotta, T et al., 1999 Breast cancer Promote Relates with doxorubicin and vincristine resistacne SANFILIPPO, O et al., 1991 NSCLC Promote Associates with both performance status and lymph node metastasis Yildirim, A et al., 2007 Bladder cancer Promote Promotes cell proliferation, migration, and invasion and relates to the poor differentiation and recurrence Zhang, Y et al., 2017 Colorectal cancer Promote Associates with clinic pathologic features and shorter overall survival Wei, F et al., 2019 Breast cancer Inhibit Modulates multi-drug resistance via inhibiting P-glycoprotein efflux Tripathi, A et al., 2016 Breast cancer Inhibit Suppresses cell proliferation and migration Pan, P et al., 2012 Erythroleukemia, breast and epiderm oid cancer Inhibit Inhibits p-glycoprotein, reverses drug resistance and restores intracellular drug accumulation Pan Q, et al., 2005 Endostatin Ovarian cancer Inhibit Inhibits the growth of ovarian cancer cell by inducing apoptosis Liu M et al., 2007 Inhibits angiogenesis by regulating bcl-2/bax and induces apoptosis Liu M et al., 2006 Non-small cell lung cancer Inhibit Inhibits cell proliferation by inducing HMGB1 Meng F et al., 2019 Lung cancer Inhibits tumor growth when combined with PD-1 inhibitor Fu S et al., 2023 Colon cancer Inhibit Inhibits growth and metastasis when combined with SU6668 and 5-FU Du Z et al., 2003 Inhibits the progress of chemically induced colon tumor Li W et al., 2005 Bladder cancer Inhibit Inhibits tumor growth by regulating MMP, VEGF and inducing apoptosis Du Z et al., 2003 Inhibits angiogenesis Wu T et al., 2020 Liver cancer Inhibit Inhibits tumor growth when combined with IL12 Wang X et al., 2005 Breast cancer Inhibit Inhibits tumor growth by inhibiting angiogenesis and increasing apoptosis Liby K et al., 2003 Lung cancer Inhibit Inhibits growth and induces apoptosis by down-regulating Bcl-2 expression Cheng X et al., 2008 Inhibits proliferation and angiogenesis, and suppresses tumor growth Luo X et al., 2014 Oral squamous cell carcinoma Inhibit Delays tumor growth and lymphatic metastasis Chung I et al., 2008 Tumstatin Breast cancer Inhibit Inhibits cell growth of breast cancer Zhong Q et al., 2011 Ovarian cancer Inhibit Promotes apoptosis Wang M et al., 2011 Inhibits tumor growth by reducing angiogenesis and angiogenic factors Zhang G et al., 2008 Laryngocarcinoma Inhibit Induces apoptosis through mitochondrial apoptosis pathway Wang L et al., 2016 Bladder cancer Inhibit Inhibits cell proliferation and induces apoptosis Li Z et al., 2011 Liver cancer Inhibit Inhibits cell proliferation and induces apoptosis through PTEN/PI3K/Akt signaling when combined with Ginsenoside Rg3 Yi T et al., 2020 Cervical cancer Inhibit Inhibits tumor growth by inhibiting angiogenesis and angiogenic factors Zhang G et al., 2007 Prostate cancer Inhibit Inhibits cell proliferation and tumor growth through apoptosis and anti-angiogenesis effects Zhang X et al., 2011 Hypervascular hepatocellular carcinoma Inhibit Inhibits vascular endothelial cells Li C et al., 2017 Glioma Inhibit Inhibits proliferation and migration by down-regulating stem cell maintenance factors Yu W et al., 2021 Colon cancer, Lewis lung cancer Inhibit Inhibits tumor growth by inhibiting angiogenesis and enhancing apoptosis when being combined with gemcitabine Yao B et al., 2005 Non-small cell lung cancer Inhibit Enhances the sensitivity of cells to cisplatin; promotes apoptosis and inhibits proliferation by inactivating Akt and ERK pathways Wang W et al., 2010 Gastric cancer Inhibit Inhibits proliferation, induces apoptosis and inhibits tumor growth Li Y et al., 2009 Inhibits proliferation and metastasis by inducing apoptosis through anoikis and PTEN/Akt pathway He Y et al., 2010 Hepatocellular carc Inoma Inhibit Inhibits tumor growth by inhibiting angiogenesis Goto T et al., 2008 Non-small cell lung cancer Inhibit Induces apoptosis, inhibits proliferation, enhances the sensitivity of cells to cisplatin by inactivating AKT pathway Wang W et al., 2015 Melanoma Inhibit Inhibits tumor progression by triggering intracellular transduction pathway Sylvie B et al., 2004 Canstatin Colon cancer Inhibit Delays tumor growth without obvious adverse reactions Wang L et al., 2009 Lewis lung cancer Inhibit Inhibits metastasis, angiogenesis and tumor growth by mediating the expression of somatostatin Lu W et al., 2011 Gastric cancer Inhibit Induces apoptosis through the mitochondrial apoptotic pathway Xing Y et al., 2019 Pancreatic cancer Inhibit Delays tumor growth by inhibiting angiogenesis He X et al., 2006 Glioma Inhibit Inhibits tumor growth by inhibiting the formation of VM-like structure Ma Y et al., 2021 Liver cancer Inhibit Inhibits tumor growth and angiogenesis by reducing the expression of Flk-1 Qi M et al., 2009 Primary oral squamous cell carcinoma Inhibit Inhibits tumor growth Hwang-Bo J et al., 2010 Esophageal cancer Inhibit Inhibits angiogenesis and tumor growth by down-regulating Flk-1 Zheng X et al., 2009 Hepatocellular carcinoma Inhibit Inhibits proliferation, migration and adhesion,promotes apoptosis and inhibits tumor growth when combined with arsenic trioxide Zhang F et al., 2020 Pancreatic cancer Inhibit Decreases microvessel density and increases apoptosis; has synergistic effects of oncolytic therapy and antiangiogenic therapy in a CRAd-Cans form He X et al., 2009 Lewis lung cancer Inhibit Inhibits tumor growth and metastasis Lu W et al., 2006 Ovarian cancer Inhibit Delays tumor growth by inhibiting angiogenesis Zhu B et al., 2009 Arresten Colon cancer Inhibit Inhibits metastasis by suppressing angiogenesis Long M et al., 2008 Gastric adenocarcinoma Inhibit Inhibits the proliferation of tumor vascular endothelial cells Lu C et al., 2005 Lung cancer Inhibit Treats cancer in a CRAd-arresten-TRAIL form Li S et al., 2015 Squamous cell carcinoma Inhibit Inhibits invasion by suppressing collagen-derived angiogenesis Mari A et al., 2012 Hexastatin Melanoma and lung cancer Inhibit Inhibits tumor growth and suppresses cell proliferation of melanoma Wen L et al., 2009 Versican Lymph node negative breast cancer Promote Promotes local invasion and metastasis by tumor remodeling of extracellular matrix through increasing versican deposition Ricciardelli C et al., 2002 Breast cancer Promote Promotes tumor progression and metastasis dos Reis D et al., 2019 Enhances the self-renewal of breast cancer through EGFR/AKT/GSK-3β (S9P) signaling, and endows it with resistance to chemotherapy drugs Du W et al., 2013 Enhances bone metastasis by promoting migration, invasion and survival of cells Du W et al., 2023 Promotes invasion, enhances cell viability, proliferation, migration and local tumor growth, enhances vascular endothelial proliferation, migration and angiogenesis Yee A et al., 2007 Promotes invasion and metastasis through EGFR signaling Du W et al., 2010 Cervical cancer Promote Enhances local invasion and decreases CD8 positive T cells Gorter A et al., 2010 Ovarian cancer Promote Promotes tumor growth Voutilainen K et al., 2003 Increases metastasis by obtaining matrix around HA/versican cells Miranda P et al., 2011 Changes tumor microenvironment and promotes tumor cancer invasion Yeung, T et al., 2011 Prostatic cancer Promote Promotes the metastasis and spread of clinical prostate cancer Ricciardelli C et al., 2007 Hepatocellular carcinoma Promote Promotes tumor development by regulating miRNA activity Fang L et al., 2013 Promotes proliferation and metastasis by activating EGFR-PI3K-AKT pathway Zhang Y et al., 2020 Gastric cancer Promote Promotes the progress of gastric cancer caused by IL-11 Zhang Z et al., 2012 Promotes proliferation, migration and invasion by overexpressing VCAN Zhai L et al., 2012 Skin cancer Promote Promotes tumor development Kunisada M et al., 2012 Melanoma Promote Promotes proliferation and migration, inhibits adhesion to type I collagen, laminin and fibronectin Hernandez D et al., 2011 Inhibit Reduces tumorigenecity Miquel-Serra L et al., 2005 Tenascin Prostate cancer Promote Is up-regulated in cancer tissue and relates to glucose uptake, lactic acid production and glycolytic enzyme expression Qian Y et al., 2022 Promotes tumor progression, enhances adhesion and colony formation through integrin α 9 β 1 Martin R et al., 2017 Breast cancer Promote Supports the tumor initiation ability through transfer niche Hassan F et al., 2016 Up-regulates the expression of growth-related genes, increases cell migration, mitosis and growth factor-dependent endothelial cell germination and elongation Jones P et al., 2000 Promotes tumor progress by immobilizing infiltrating T lymphocytes through CXCL12 Jones F et al., 2000 Contributes to the invasion behavior of tumor cells Scherberich A et al., 2005 Promotes therapy-resistant metastasis Insua-Rodriguez J et al., 2018 Increases invasion by promoting Tenascin C inclusion in extracellular vesicles Campos A et al., 2023 Mediates lung metastasis Taraseviciute A et al., 2006 Promotes invasion and proliferation Alcock R et al., 2005 Promotes cell proliferation Swierczynski S et al., 2011 Promotes invasion and proliferation Alcock R et al., 2005 Colon cancer Promote Promotes tumorigenesis by activating matrix fibroblasts based on 1- integrin activation Fujita M et al., 2019 Promotes invasion through EMT regulation and acts as a specific new indicator Takahashi Y et al., 2013 Promotes EMT-like changes and proliferation and leads to poor prognosis Yang Z et al., 2018 Drives tumor progression and participates in CSC characteristics through HH signaling Yang Z et al., 2020 Gastric cancer Promote Inhibits the angiogenesis simulation by suppressing ERK-triggered EMT Xing K et al., 2021 Oral squamous cell carcinoma Promote Promotes metastasis by enhancing the immunosuppressive lymphatic matrix through CCL21/CCR7 signaling Caroline S et al., 2020 Triple negative breast cancer Promote Promotes the resistance to T cell-mediated cytotoxicity by blocking the degradation of Tenin C Li Z et al., 2020 Endometrium cancer Promote Promotes tumor progress by immobilizing infiltrating T lymphocytes through CXCL12 Murdamoothoo D et al., 1996 Ovarian cancer Promote Promotes patients’ survival and supports spheroids formation and tumor progression Roders A et al., 2024 Glioblastoma Promote Promotes invasion of glioblastoma Hirata E et al., 2009 Induces excessive proliferation of glioblastoma cells Fujita M et al., 2019 Laryngocarcinoma Promote Promotes proliferation and migration in an autocrine way Toshimichi Y et al., 1999 Osteosarcoma Promote Promotes distant metastasis of osteosarcoma Tanaka M et al., 2000 Pancreatic ductal adenocarcinoma Promote Hedgehog signaling stimulates Tenascin C to promote invasion through Annexin A2 Foley K et al., 2017 Squamous cell carcinoma of head and neck Promote Migration of cancer cells is dependent on tenascin-C expression Thomas C et al., 2016 Esophageal squamous cell carcinoma Promote Enhances the dry-like characteristics of cancer and promotes EMT-like changes through Akt/HIF1α axis Yang Z et al., 2019 Neuroendocrine tumor Promote Down-regulation of DKK1 is an important mechanism for TNC to enhance tumor progression by providing tumor microenvironment that promotes angiogenesis Falk S et al., 2014 Pancreatic cancer Promote Suppresses apoptosis through activation of ERK/NF-κB pathway Shi M et al., 2015 Promotes tumor progress Chen J et al., 2009 Promotes the diffusion and metastasis by affecting the proliferation, migration and adhesion Berchtold S et al., 2011 Bladder cancer Promote Mediates malignant behavior through syndecan-4 and NF-κB signaling Guan Z et al., 2022 Matrikines Melanoma Promote Up-regulates migration and promotes chemotaxis, mitosis and metastasis Tran K et al.,2005 The role and mechanisms of extracellular matrix (ECM) and related proteins in cancer Ippolito, L et al., 2024 Head and neck squa mous cell carcinoma Squamous cell carcinoma, prostate cancer, colorectal cancer, lung cancer Breast, hepatocellular, lung and prostate cancer , melanoma and multiple myeloma SANFILIPPO, O et al., 1991 Inhibits growth and metastasis when combined with SU6668 and 5-FU Inhibits tumor growth by inhibiting angiogenesis and enhancing apoptosis when being combined with gemcitabine Hepatocellular carc Inoma Voutilainen K et al., 2003 Scherberich A et al., 2005 Swierczynski S et al., 2011 Toshimichi Y et al., 1999

Cancer is still the second leading cause of death after cardiovascular disease in the world, the main reason is that about 50% of cancers are diagnosed at a late stage. The limited efficacy of existing treatment methods and the high failure rate in drug development make the situation more complex, and there is an urgent need for a better understanding of disease mechanisms, the development of early detection technology, and cancer chemoprevention strategies. Here, we systematically analyzed the role of inflammation and its related molecules in tumors. We expect that a substantial amount of information and intricacies continually uncovered in the area will eventually be condensed into a few key principles that regulate the molecular and cellular processes underpinning inflammation that promote tumor growth. The role of inflammatory molecules in cancer has attracted the researchers’ attention during the past decades. New insights into the pro- or anti-tumor effect in the tumor and its microenvironment have given impetus to drug discovery and patient evaluation of inflammation-directed strategies. For example, as the most effective and widely distributed family of cytokines, IFN-Is, or type I interferons, are essential for launching a successful anti-tumor response. Antigen-presenting cells require interferon-alpha to trigger T cell responses; additionally, IFN-Is directly boost CD8 + T cell activity and cytotoxicity, stimulate CD4 + Th1 cell development, augment cytotoxicity from natural killer cells, and limit regulatory T cells. However, IFN-Is induce the expression of negative regulatory molecules, which can reduce immunological responses and induce fatigue, thus facilitating the growth of tumors. Besides, other inflammatory molecules such as interleukins, tumor necrosis factors, colony-stimulating factors, chemokines, and inflammasomes also showed multifaceted effects in cancer. The two-side effect may depend on the cancer type, time, cells present, total IFN-I signal levels, and others. Therefore, further studies are needed to dissect the dual role of these inflammatory molecules in different cancer models, which will enable the identification of novel molecular and immunological targets and lead to the development of novel therapeutic strategies. Recently, researchers created a portable smart blue-light controlled (PSLC) gadget based on optogenetic technology. The findings demonstrate that blue light can efficiently control pro-inflammatory cytokine expression in both in vitro and in vivo settings, which offers a unique strategy for cytokine therapy [ 452 ]. FDA-approved non-anticancer drugs- “old medicine”, have obvious advantages in anti-tumor treatment—“new use”, because FDA-approved drug applications could better avoid numerous obstacles and uncertainties in every step of converting drugs into clinical applications. This suggests that the application of non-anticancer drugs may be a promising strategy for cancer chemoprevention. The evident role of inflammation in cancer development and progression prompted the application of anti-inflammatory medications as a therapeutic strategy. While the application of anti-inflammatory drugs in clinical antitumor therapy still needs to overcome several obstacles. 1) Targeted delivery to the cancerous cell. Although the anti-inflammatory medications now approved by the FDA are undoubtedly effective, their off-target effects and toxicities make them less desirable options for cancer therapy when taken at the current dosages and frequency. Rather, to improve drug targetability and reduce off-target adverse effects, recent developments in nanotechnology have facilitated a paradigm shift away from traditional anti-inflammatory medications and toward anti-inflammatory nano-therapeutics in cancer therapy. However, the field of anti-inflammatory nanomedicines is still in its infancy with little commercial application, and there is a great need to consider and identify the issues with nano-inflammatory therapies to aid in the practical clinical translation of commercially available anti-inflammatory nanotherapeutics. 2) Tumor cells have different or even opposite responses to these anti-inflammatory drugs. Abundant evidence indicates that anti-inflammation drugs are promising candidates for preventing carcinogenesis and cancer recurrence because of their availability and relatively low occurrence of side effects compared to other chemotherapeutic drugs. Nevertheless, due to the paucity of information and the complexity of carcinogenesis, these anti-inflammation drugs showed different or even inverse effects. Well-designed, long-term clinical trials are required to ascertain the clinical application potential of these medications, and additional trials are required to investigate the doses, kinds, and length of response of these drugs. 3) The side effects after long-term use. Although the FDA-approved anti-inflammatory drugs have far fewer side effects than chemotherapeutics, some anti-inflammatory drugs, such as aspirin, also showed obvious side effects after long-term use. The main side effects of NSAIDs are cardiovascular (CV) and renal adverse effects. While the main side effects of seroidal anti-inflammatory drugs such as glucocorticoids (GRs) are diabetes, glaucoma, and suppression of the hypothalamic–pituitary–adrenal axis, among others. NSAIDs cause cell death by directly targeting mitochondria, while NSAIDs have been shown to enhance mitochondrial health in dose-dependent ways [ 453 ], which suggesting that future research should focus on comparing equipotent dosages of these drugs. Additionally, it’s important to assess the alleviation of symptoms. There are ongoing efforts to develop selective GR agonists (SEGRAs) with the hypothesis that they are safer than traditional glucocorticoids. To support this hypothesis, appropriate in vitro and in vivo studies are needed to provide reliable experimental results. 4) Patients continue to experience other thromboembolic events despite aspirin therapy, which is known as aspirin resistance (AR). Besides, anti-inflammatory drugs may lead to a degree of drug resistance. For example, dexamethasone can increase the resistance of human tumor cells to ionizing radiation and chemotherapy [ 454 ]. Hence, larger-scale adoption of the chemoprevention strategy is likely to require improved identification of individuals for whom the protective benefits outweigh the harms. Such a precision medicine approach may emerge through further clarification of these anti-inflammatory drugs’ mechanism of action.

German physician Rudolf Virchow first reported the relationship between inflammation and tumors in the nineteenth century [ 1 ]. Chronic inflammatory processes are a fundamental innate immune response to perturbed tissue homeostasis and affect multiple stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis [ 2 ]. It is estimated that 15–20% of tumor-related deaths are linked to inflammation. Recently, a growing body of evidence from basic research and clinical data indicates that inflammatory molecules and inflammation pathways can promote the occurrence and progression of various tumors. Pro-inflammatory cytokines, like interleukin (IL)−6, IL-1β, and tumor necrosis factor-α (TNF-α), as well as transcription factors, like nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3), are key players in this relationship [ 3 – 7 ]. Encouraged by pro-inflammatory cytokines, NF-κB and STAT3 can control the expression of target genes, the majority of which are carcinogenic, and increase the ability of cancer cells to survive, proliferate, invade, and spread [ 8 – 10 ]. It is now well-acknowledged that chemicals and processes associated with inflammation can be valuable targets for cancer prevention and treatment. During the past decades, there has been strong epidemiological evidence showing that nonsteroidal anti-inflammatory drugs (NSAIDs), especially aspirin, have been associated with a reduction in the incidence and mortality of a variety of types of cancer with long-term use, especially colorectal cancer (CRC) [ 11 , 12 ]. In 2016, the US Preventive Services Task Force (USPSTF) recommended low-dose aspirin for primary prevention of CRC for adults aged 50–59 years [ 13 ]. Besides, low-dose aspirin or non-aspirin NSAIDs intake is inversely related to gastric cancer risk based on multiple meta-analyses [ 14 – 16 ]. Recent research based on electronic endoscopy [ 20 ] and territory-wide healthcare databases [ 17 ] also verified these results. Except for CRC and gastric cancer, aspirin use also reduces the incidence and mortality of endometrial cancer [ 18 ], breast cancer [ 19 , 20 ], esophageal cancer [ 21 ], liver cancer [ 22 ], and more. Besides, other NSAIDs and steroid anti-inflammatory drugs also have obvious anti-tumor effects. For example, the novel indomethacin derivative CZ-212–3 showed antitumor effects in castration-resistant prostate cancer [ 23 ]; indomethacin sensitized death receptor 5 (DR5)-deficient tumor cells to adoptive T-cell therapy [ 24 ]; indomethacin-loaded nanocapsules treatment reduced glioblastoma growth in a rat model [ 25 ]. These suggest that FDA-approved NSAIDs and steroid anti-inflammatory drugs are promising candidate drugs for cancer prevention and treatment. In this review, the detailed information on cytokines and their function in tumorigenesis are comprehensively analyzed, and their potential as therapeutic targets for cancer treatment and chemoprevention and their inhibitor/agonists applied in preclinical and clinical studies are also clarified. Uncovering the exact mechanisms of inflammation and inflammatory factors enabled the development of novel, tailored, and highly effective cancer prevention and treatment strategies. We also discussed Food and Drug Administration (FDA)-approved non-anti-tumor drugs that may help prevent and treat cancer-related chronic inflammation, such as aspirin, indomethacin, celecoxib, and other NSAIDs and steroidal anti-inflammatory drugs. The effects of these medicines on proinflammatory cytokines and inflammation-related pathways are addressed, and typical clinical study data are presented. According to data from the current review, agents that target chronic inflammation may have a wide range of applications in the future for the prevention and treatment of cancer.