HPV-driven inflammatory pathways in ovarian carcinogenesis: molecular mechanisms and emerging therapeutic interventions.

Human papillomavirus (HPV) has been widely acknowledged for its crucial role in the pathogenesis of cervical cancer, particularly due to high-risk strains such as HPV 16 and HPV 18 [ 68 – 70 ]. Recent studies have also highlighted a potential involvement of HPV in the development of OC [ 71 ]. The molecular mechanisms through which HPV contributes to ovarian carcinogenesis are multifactorial, encompassing viral oncoprotein functions, immune system modulation, inflammatory processes, and genomic alterations [ 72 ]. This section examines the molecular processes by which HPV induces oncogenesis in ovarian tissue and explores their implications for OC development. The oncogenic potential of HPV is primarily attributed to its oncoproteins E6 and E7 [ 73 , 74 ]. These proteins target key tumor suppressors, including p53 and retinoblastoma protein (pRb), thereby disrupting cell cycle regulation and apoptosis. E6 binds to and promotes degradation of p53, preventing normal cell-cycle arrest and apoptosis in response to DNA damage [ 75 ]. Consequently, HPV-infected cells bypass checkpoints, accumulate mutations, and proliferate uncontrollably—hallmarks of malignant transformation. Similarly, E7 binds to pRb, releasing the E2F transcription factors, which promotes cell cycle progression into the S phase, driving uncontrolled proliferation. In OC, persistent HPV infection may result in the expression of E6 and E7, contributing to genomic instability and malignant transformation [ 76 , 77 ]. The integration of HPV DNA into the host genome plays a key role in the persistence of the virus and the continuous expression of these oncoproteins, which are typically regulated by the E2 protein [ 78 ]. Loss of this regulation can lead to prolonged cellular transformation, fostering oncogenesis. This mechanism, while well-established in cervical cancer, may also be relevant in OC, particularly when HPV DNA integration is detected in ovarian tumor tissues [ 79 ]. Chronic inflammation induced by persistent HPV infection plays a critical role in ovarian carcinogenesis. HPV infection triggers an inflammatory response in ovarian tissue, leading to the recruitment of immune cells and the release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-8. These cytokines promote a pro-tumorigenic microenvironment by causing cellular damage, enhancing genomic instability, and supporting the survival and proliferation of abnormal cells [ 80 ]. Additionally, the inflammatory environment can impair immune surveillance, further facilitating the transformation of ovarian cells into cancerous cells [ 81 ]. One of the key features of HPV-associated oncogenesis is the virus’s ability to modulate the immune response. HPV has evolved several strategies to evade immune detection and clearance, allowing the virus to persist in infected tissues [ 82 , 83 ]. The E6 and E7 oncoproteins, in particular, contribute to immune evasion by suppressing the activity of cytotoxic T lymphocytes (CTLs), which are responsible for eliminating HPV-infected cells. HPV can also inhibit the production of type I interferons (e.g., IFN-α and IFN-β), which are essential for the immune system’s ability to clear viral infections [ 84 , 85 ]. By preventing the activation of these immune responses, HPV ensures the persistence of infection, which is crucial for its oncogenic potential [ 86 ]. Additionally, HPV infection may alter the tumor microenvironment, further promoting OC progression [ 87 ]. In HPV-infected tissues, immune cells such as regulatory Tregs and TAMs may be recruited to the site of infection. These immune cells contribute to an immunosuppressive environment that enables the tumor to evade immune detection and continue to grow [ 88 , 89 ]. The upregulation of immune checkpoint molecules, such as PD-L1, has been observed in HPV-infected tumor cells, including those in OC. The interaction between PD-L1 on tumor cells and PD-1 on T cells inhibits T-cell-mediated immune responses, further facilitating immune evasion [ 90 , 91 ]. In addition to immune modulation, HPV infection may contribute to OC progression through epigenetic alterations. The integration of HPV DNA into the host genome can lead to changes in gene expression without altering the underlying genetic code. These epigenetic modifications, including DNA methylation and histone modifications, can silence tumor suppressor genes or activate oncogenes, facilitating the transformation of normal cells into malignant ones [ 92 ]. The methylation of key tumor suppressor genes, such as PTEN and p16INK4a, has been associated with the development of OC, further supporting the role of HPV in driving oncogenesis [ 93 ]. The role of HPV in OC is further complicated by its interaction with the ovarian microbiome. Dysbiosis, or an imbalance in the microbial community, has been observed in women with OC. Certain bacterial species, such as Lactobacillus, play a role in maintaining the mucosal barrier, and their loss during HPV infection may facilitate cancer development [ 94 , 95 ]. HPV infection may exacerbate microbial dysbiosis, creating an inflammatory environment that enhances tumorigenesis [ 96 ]. The interplay between HPV infection and the microbiome represents a novel avenue for research into potential therapeutic strategies [ 97 ].

In HPV-associated ovarian tumors, the virus employs various immune evasion strategies to persist in the host and contribute to tumor progression. These mechanisms help HPV-infected cells escape detection and destruction by the host’s immune system, allowing the tumors to thrive [ 98 ]. The virus manipulates both innate and adaptive immune responses, leading to a pro-tumor environment within the TME. Understanding these mechanisms is crucial for the development of therapeutic strategies to counteract HPV-associated OC [ 99 ]. A primary mechanism of immune evasion in HPV-associated ovarian tumors involves the action of the viral oncoproteins E6 and E7. These oncoproteins disrupt several key components of the host’s immune system, leading to the loss of cell cycle control [ 100 ]. As a result, the action of HPV proteins causes the accumulation of genetic mutations within the cells. These mutations collectively contribute to tumorigenesis, the transformation of normal cells into cancerous ones, while also helping the infected cells evade immune detection [ 76 ]. In addition to its direct effects on tumor suppressors, HPV also influences the immune microenvironment to enhance its persistence [ 99 ]. One of the immune evasion strategies employed by HPV is the upregulation of immune checkpoint molecules, particularly PD-L1. The expression of PD-L1 in tumor cells interacts with the PD-1 receptor on T cells, leading to immune exhaustion and preventing the activation of CTLs. This inhibition of T-cell activity is crucial for HPV to escape immune surveillance, allowing the tumor to evade detection and continue to grow. In HPV-associated ovarian tumors, elevated PD-L1 expression has been correlated with poor prognosis, highlighting its role in promoting immune tolerance and tumor progression [ 101 – 103 ]. Another immune evasion mechanism in HPV-associated ovarian tumors is the alteration of antigen presentation [ 83 ]. The immune system’s ability to recognize and attack HPV-infected cells relies on the presentation of viral antigens on the surface of tumor cells by major histocompatibility complex (MHC) class I molecules. However, HPV-infected cells often downregulate the expression of MHC class I molecules, reducing their visibility to CTLs and allowing the tumor cells to evade immune recognition. This downregulation of MHC class I molecules is a critical mechanism that hinders the immune system’s ability to target and eliminate HPV-infected cells [ 104 , 105 ]. Additionally, the HPV oncoproteins interfere with the immunoproteasome, further suppressing antigen presentation [ 106 ]. The TME in HPV-associated OC is also shaped by the infiltration of immunosuppressive cells [ 107 ]. Tregs and MDSCs are frequently recruited to the TME, where they suppress the activation of effector immune cells, including CTLs and NK cells [ 108 , 109 ]. The increased presence of Tregs in the TME of HPV-associated ovarian tumors helps create an immunosuppressive environment that prevents effective immune responses. These cells secrete immunosuppressive cytokines such as TGF-β and IL-10, further inhibiting immune cell activity. The manipulation of Tregs by HPV contributes to immune tolerance, enabling the tumor to escape detection and proliferate unchecked [ 110 , 111 ]. Furthermore, HPV infection induces chronic inflammation in the TME, which plays a significant role in immune evasion. The persistent infection triggers the production of pro-inflammatory cytokines such as IL-6, TNF-α, and TGF-β, which further suppress immune responses and promote tumor cell survival [ 112 , 113 ]. Chronic inflammation also leads to the generation of reactive oxygen species, contributing to DNA damage and genomic instability, which further promote the transformation of normal cells into cancerous ones. These inflammatory mediators create an environment that supports tumor progression while simultaneously impairing the immune system’s ability to mount an effective defense [ 114 , 115 ]. HPV also exploits the innate immune system to promote immune evasion. One of the key pathways targeted by HPV is the cGAS-STING pathway, which normally detects cytosolic DNA and activates an innate immune response, including the production of type I interferons. In HPV-associated ovarian tumors, this pathway is frequently suppressed, preventing the activation of type I interferons and other immune-stimulating cytokines. By inhibiting the cGAS-STING pathway, HPV can evade detection by the innate immune system, allowing the tumor to escape immune responses and continue its progression [ 116 , 117 ]. Additionally, HPV has been shown to downregulate Toll-like receptors (TLRs), which are essential for detecting pathogen-associated molecular patterns and initiating immune responses. This reduction in TLR expression further weakens the immune system’s ability to recognize and respond to the infection [ 118 , 119 ]. The modulation of the immune response by HPV also involves the regulation of various immune checkpoints. Beyond PD-L1, other checkpoint proteins, such as CTLA-4 and LAG3, are upregulated in HPV-associated ovarian tumors. These immune checkpoints contribute to the suppression of T-cell activation, further enhancing immune evasion [ 120 , 121 ]. HPV infection has been shown to induce the expression of these checkpoint proteins, impairing the ability of T cells to mount an effective anti-tumor response. The upregulation of these checkpoint proteins represents an additional layer of immune suppression in HPV-related OC [ 122 ]. The dysregulation of immune signaling pathways in HPV-associated ovarian tumors also involves the suppression of apoptosis. This suppression prevents the initiation of programmed cell death in response to immune attack. By inhibiting apoptosis, HPV-infected cells can survive and proliferate despite the presence of immune cells that would normally recognize and eliminate them [ 123 , 124 ].

Oncogenesis requires HPV infection alone, but it is not enough; sex hormones—particularly progesterone and estrogen—play a crucial role as cofactors that influence viral gene expression, immune evasion, and epithelial change [ 162 , 163 ]. Sex hormones, notably estrogen and progesterone, are produced from cholesterol via a sequence of biochemical processes involving cytochrome P450 enzymes such as CYP11A1 and CYP19A1, which convert cholesterol to pregnenolone and then to estradiol and progesterone. Nuclear receptors such as estrogen receptors (ERα and ERβ) and progesterone receptors (PR-A and PR-B) regulate gene expression in ovarian tissue. Overexpression of ERα in ovarian cancer promotes proliferation, angiogenesis, and immune evasion via activating the PI3K/Akt and MAPK pathways [ 164 ]. Progesterone signaling, on the other hand, is more complicated; while PR expression is linked with a better prognosis in HGSOC, the downstream effects are dependent on isoform balance and tumor context [ 165 ]. Estrogen contributes to the persistence and transformation of HPV in hormone-sensitive tissues by increasing the transcription of HPV oncogenes E6 and E7 through estrogen-responsive regions in the viral genome [ 162 ]. Moreover, progesterone can alter HPV activity, and prolonged use of progestin-based birth control has been associated with a higher risk of cervical cancer in women who are HPV-positive [ 163 ]. Chronic inflammation is one of the main factors influencing the growth of tumors in the ovarian microenvironment [ 1 ]. The NF-κB and STAT3 pathways are activated by increased cytokines such IL-6, TNF-α, and IL-8, which promote angiogenesis, proliferation, and immunological suppression. By boosting inflammatory signaling and vascular remodeling, estrogen can increase VEGF and IL-6 through ERα-mediated transcription [ 1 ]. Progesterone inhibits NF-κB activation by downregulating COX-2 and pro-inflammatory cytokines, boosting IκBα expression, and decreasing nuclear translocation of p65 [ 166 ]. The COX–prostaglandin (COX–PG) pathway serves as a key regulator of both inflammation and cancer progression. Elevated expression of COX-2, which has been documented in numerous malignancies, facilitates tumor advancement by promoting metastasis, inhibiting apoptosis, and driving angiogenesis as well as uncontrolled cell proliferation. Importantly, HPV oncoproteins (E5, E6, and E7) have been shown to enhance this pathway by upregulating COX-2 and increasing levels of prostaglandin E (PGE), thereby reinforcing oncogenic signaling [ 13 ]. Ovarian tumors with high levels of inflammatory gene expression have poor response to immunotherapy, decreased cytotoxic T cell activity, and enhanced M2 macrophage infiltration, according to transcriptomic studies [ 167 ]. Regulatory Tregs and TAMs are prevalent in the ovarian tumor microenvironment and inhibit anti-tumor immunity. TAMs and dendritic cells produce more PD-L1 when estrogen is present, which promotes immunological escape. Inhibiting NK cell cytotoxicity and promoting Th2 cytokine profiles, progesterone-induced PIBF further reduces immunological responses [ 168 ]. The ERα and ERβ estrogen receptors, which are present in cervical epithelial cells and frequently increased in HPV-positive tissues, constitute the mechanism by which estrogen works [ 162 ]. According to research, estradiol inhibits apoptosis and promotes cell cycle progression by increasing the transcription of HPV oncogenes E6 and E7, which inactivate tumor suppressor p53 and Rb, respectively. Cervical cancer only appeared in transgenic mouse models expressing HPV16 E6/E7 after the mice were exposed to estrogen on a long-term basis, indicating that it is a co-carcinogene [ 169 ]. The interplay between HPV oncoproteins and estrogen signaling pathways in ovarian carcinogenesis is summarized in Fig. 1 . Fig. 1 Estrogen signaling crosstalk with HPV oncoproteins in ovarian tumor cells Estrogen signaling crosstalk with HPV oncoproteins in ovarian tumor cells Estrogen–ER interactions at estrogen response elements (EREs) enhance the transcription of oncogenic targets such as Cyclin D1, MYC, BCL-2, and VEGF, collectively reinforcing proliferative signaling, apoptosis resistance, and angiogenic potential. Concurrently, estrogen moves to the nucleus and interacts with the viral DNA, raising levels of E6/E7 proteins; E6 breaks down p53, and E7 blocks Rb, leading to stronger NF-κB/COX-2 activity that worsens ongoing inflammation, cancer cell survival, and changes in blood vessel patterns in the ovarian tumor microenvironment (TME). The convergence of these viral and hormonal pathways establishes a permissive microenvironment for sustained cellular survival, genomic instability, and malignant transformation of ovarian epithelial cells. Furthermore, the long control region (LCR) of the HPV genome has been found to contain estrogen-responsive regions, indicating that estrogen-bound ER complexes directly regulate the transcription of viral genes [ 170 ]. Progesterone has a more complex effect on HPV biology, but it also affects it through progesterone receptors (PR-A and PR-B) [ 163 ]. According to some research, progesterone may promote epithelial differentiation and reduce inflammation, while other studies show that progestogenic contraceptives may increase the risk of cervical cancer in women with HPV, particularly if used for an extended period of time. Progesterone receptors have been demonstrated to bind to HPV genome regulatory regions, which may alter the expression of E6/E7 oncogenes [ 171 ]. Remarkably, HPV oncoproteins themselves have the ability to change hormone receptor expression and location. For instance, E6 and E7 promote viral persistence and cellular transformation by increasing the expression of ERα and PRLR and moving them closer to the nucleus, which increases their transcriptional activity [ 169 ]. According to clinical research, women with HPV have higher amounts of estradiol in their blood, and higher levels of estradiol are associated with a higher chance of viral persistence over a 12-month period—a crucial stage in the development of cancer [ 163 ]. Even though other studies did not find a direct correlation between progesterone levels and HPV persistence, its immunomodulatory actions might still add to the overall risk profile, particularly when combined with the use of hormonal contraceptives [ 163 ]. Progesterone (P4), a steroid hormone primarily produced in the corpus luteum and adrenal glands, plays a vital role not only in reproductive processes but also in modulating immune responses [ 172 ]. Beyond its well-established functions in regulating the menstrual cycle and supporting pregnancy, progesterone exerts significant anti-inflammatory effects via both genomic and non-genomic pathways [ 173 ]. These effects are mediated through nuclear progesterone receptors (nPRs), membrane-associated progesterone receptors (mPRs), and various intracellular chaperone proteins, which together influence numerous inflammatory and immune regulatory circuits [ 174 ]. Through genomic mechanisms, progesterone activates its nuclear receptors—PR-A and PR-B which act as ligand-dependent transcription factors. Upon hormone binding, these receptors move into the nucleus and alter the expression of genes involved in immune regulation and maintaining tissue integrity [ 172 ]. A key anti-inflammatory function of progesterone involves inhibition of the NF-κB pathway. By blocking the translocation of the NF-κB p65 subunit into the nucleus, progesterone downregulates the expression of key pro-inflammatory mediators such as TNF-α, IL-6, and COX-2, thereby limiting inflammation [ 175 ]. Non-genomic signaling is triggered through membrane-bound receptors such as mPRs and PGRMC1, which activate rapid signaling cascades including PI3K/Akt, MAPK/ERK, and STAT3 [ 174 ]. These pathways contribute to immune suppression, reduced cytokine production, and increased cell survival. Progesterone also forms complexes with molecular chaperones like HSP70, HSP90, and immunophilins FKBP51 and FKBP52. These complexes assist in stabilizing receptor structure and facilitating transcriptional regulation. FKBP51, in particular, is known to play a role in modulating stress and inflammatory responses and may enhance progesterone’s anti-inflammatory effects when bound to its receptor [ 173 ]. A major mediator of progesterone’s immunosuppressive activity is progesterone-induced blocking factor (PIBF), a protein whose expression is upregulated following PR activation. PIBF suppresses T cell activation, lowers the production of pro-inflammatory cytokines, and promotes the secretion of IL-10, a key cytokine involved in immune tolerance. This function is particularly important during pregnancy and cancer progression, where controlled immune responses are necessary for fetal or tumor survival [ 168 ]. Progesterone also inhibits activation of the NLRP3 inflammasome, a protein complex responsible for processing and releasing IL-1β. By promoting autophagy and preventing inflammasome assembly, progesterone reduces inflammation and tissue damage [ 176 ]. However, in progesterone-resistant conditions such as endometriosis and specific ovarian cancer subtypes, these anti-inflammatory effects are weakened due to disrupted receptor signaling or altered receptor expression [ 165 ]. In ovarian cancer, the role of progesterone is nuanced and depends on multiple factors. Elevated progesterone levels are generally linked to a reduced cancer risk in premenopausal women. Yet, within the tumor microenvironment, the hormone’s effects are shaped by the expression of PR isoforms, presence of BRCA mutations, and tumor histology [ 165 ]. Progesterone may help suppress inflammation and modulate immune tolerance, but its benefits are diminished in tumors that exhibit progesterone resistance. Furthermore, it can counteract the inflammatory actions of estrogen receptor β (ERβ), contributing further to its immunoregulatory functions [ 164 ]. From a therapeutic standpoint, progesterone and its synthetic derivatives are being investigated as potential adjuncts in treating hormone-responsive cancers. Selective progesterone receptor modulators (SPRMs) may provide therapeutic benefit in PR-positive ovarian cancers, especially when combined with immune checkpoint inhibitors targeting PD-1/PD-L1 signaling pathways [ 177 ]. A vital cellular mechanism, autophagy uses lysosomal pathways to break down and recycle intracellular pathogens, misfolded proteins, and damaged organelles in order to maintain homeostasis. It is essential for cell survival, immunological modulation, and inflammatory management and is especially active in stressful situations such oxidative stress, hypoxia, and food deprivation [ 178 ]. The phagophore membrane is nucleated by Beclin-1 and VPS34, the autophagosome is elongated and closed by ATG proteins and LC3 lipidation, the autophagic pathway is initiated by mTOR inhibition and ULK1 activation, and it culminates in fusion with lysosomes for the breakdown and recycling of cellular components [ 178 ]. Progesterone and other steroid hormones, as well as important intracellular signaling pathways like PI3K/Akt/mTOR, AMPK, and MAPK, affect autophagy. By blocking the mTOR pathway and activating membrane-associated receptors and its nuclear receptors (PR-A and PR-B), progesterone (P4) can encourage the start of autophagy. Additionally, it promotes the transcription of genes linked to autophagy, including BECN1, ATG5, and LC3B, which helps reproductive tissues and hormone-sensitive cancers engage in autophagic activity [ 179 ]. While progesterone inhibits mTORC1, enabling ULK1 activation and autophagosome formation, estrogen increases PI3K via ERα, boosting mTORC1 activity and limiting autophagy. Autophagy reduces inflammation and IL-1β release by inhibiting the activation of the NLRP3 inflammasome. To maintain ovarian homeostasis, autophagy must be regulated by hormones. Epithelial hyperplasia and inflammation result from progesterone-induced autophagy and decidualization being disrupted by FIP200 deletion. Through mTOR activation, estrogen inhibits autophagy, which promotes tumor development and chemoresistance. Inflammatory signals alter hormone receptors themselves. By increasing ERα and PR expression, IL-6 and TNF-α can improve tumor cells’ hormone responsiveness. On the other hand, HPV oncoproteins E6/E7 enhance the production of ERα and PRLR, hence intensifying hormonal signaling and facilitating transformation. Immune tolerance, embryo implantation, and decidualization are among the physiological functions in the uterus that depend on progesterone-induced autophagy. Autophagy plays a crucial role in progesterone-mediated reproductive function, as demonstrated by experimental research that shows deletion of autophagy-related proteins, such as FIP200, reduces progesterone responsiveness and causes pathological inflammation [ 179 ]. Autophagy has two distinct and context-dependent functions in ovarian cancer. Under certain hormonal circumstances, it also aids in immunological modulation, inflammatory suppression, and tumor inhibition, even though it may promote tumor cell survival under metabolic stress. By downregulating mTOR signaling and activating ULK1, progesterone has been demonstrated to cause autophagy in ovarian cancer cells, promoting the production of autophagosomes and cellular recycling. Progesterone promotes cellular adaptability to stress and aids in tumor suppression by increasing the expression of genes linked to autophagy through PR-mediated transcriptional control [ 176 ]. One important way that progesterone reduces inflammation is by suppressing the NLRP3 inflammasome, which is mediated by autophagy. Autophagy reduces inflammation by limiting the release of IL-1β and breaking down the components of the inflammasome. In progesterone-sensitive ovarian cancers, where P4 helps create an immunologically quiescent milieu, this pathway is especially pertinent. On the other hand, progesterone-resistant tumors might have compromised autophagy, which could result in immune evasion, chronic inflammation, and tumor growth [ 176 ]. Established investigations in ovarian cancer (OC) affirm autophagy’s pivotal role in modulating progesterone (P4) signaling and therapeutic resistance, providing a mechanistic foundation for its dysregulation in tumor progression. Zhu et al. elucidated that hyperoside, a flavonoid compound, elicits PGRMC1-dependent autophagy in OC cell lines (SKOV3 and OVCAR3), thereby augmenting cisplatin sensitivity. Specifically, hyperoside facilitated LC3B-I to LC3B-II conversion and autophagosome formation, colocalizing with PGRMC1; overexpression of PGRMC1 amplified autophagy-induced apoptosis via AKT/Bcl-2 inhibition, whereas knockdown abrogated these effects. In cisplatin-resistant variants exhibiting elevated PGRMC1, hyperoside restored platinum responsiveness, underscoring PGRMC1’s established mediation of progesterone-driven chemoresistance through autophagic pathways and proposing its targeting as an adjuvant strategy for platinum-based regimens [ 180 ]. Complementing this, Esmaeilian et al.established autophagy’s indispensable function in ovarian P4 biosynthesis using ex vivo explants and granulosa cells. Pharmacological blockade (e.g., chloroquine) or genetic silencing (Beclin1/ATG5) curtailed gonadotropin-stimulated P4 production by 50–70%, predominantly via impaired lipophagy and cholesterol mobilization; similar deficits in luteinized granulosa cells from luteal phase defect patients linked autophagic flux disruptions to reproductive pathologies. These findings solidify autophagy as a core regulator of steroidogenesis in ovarian tissues, with implications for OC where progesterone homeostasis influences tumor survival [ 181 ]. An integrative review by Afzal et al. further synthesizes these mechanisms, highlighting FSH-induced Beclin-1 activation in granulosa cells as a driver of lipophagic cholesterol supply for P4 synthesis. Perturbations in mTOR-autophagy signaling—prevalent in OC precursors—destabilize this axis, fostering follicular atresia and pro-inflammatory microenvironments; thus, autophagy enhancement may preserve fertility via P4 restoration, while inhibition in malignancies could disrupt progesterone-dependent survival circuits [ 182 ]. While these OC-centric data are robust, extensions to HPV-driven contexts remain speculative, drawing primarily from cervical models. Wang et al. demonstrated that HPV16 oncoproteins E6/E7 potently induce autophagic flux in cervical epithelia (SiHa, CaSki lines) via Atg9B and LAMP1 upregulation, as evidenced by diminished LC3-II/GFP-LC3 puncta upon E6/E7 silencing and enhanced lysosomal fusion upon ectopic expression in HEK293 cells. Transcriptomic and CRISPR validation positioned Atg9B as a key effector for stress-induced survival. Intriguingly, the authors hypothesize progesterone amplification of this pathway through PGRMC1, noting E6’s selective degradation of nuclear progesterone receptors (sparing membrane isoforms), which may sustain autophagy-mediated immune evasion in HPV oncogenesis [ 183 , 184 ].

The redox state is the balance between reactive oxygen species (ROS) and the antioxidants that neutralize them. Typically, ROS are produced in small amounts within cellular structures such as the mitochondrial respiratory chain and the endoplasmic reticulum, where they perform vital physiological roles at low levels. The cell’s antioxidant defense system mainly maintains this balance between ROS generation and elimination [ 225 , 226 ]. Oxidative stress happens when ROS production surpasses the cell’s capacity to neutralize it with antioxidants, leading to an excessive generation of ROS. In other words, oxidative stress describes an imbalance between the creation and breakdown of ROS in biological systems. ROS are highly reactive, oxygen-containing molecules, including hydroxyl radicals (HO • ) and superoxide anions (O2 •− ). These molecules interact with essential cellular components, causing DNA base oxidation, lipid peroxidation, and protein carbonylation, which damage their structure and impair their normal functions. This leads to the initiation, promotion, and progression phases of tumor development. In the ovary, ROS play critical physiological and regulatory roles in meiosis, ovulation, and the maintenance and regression of the corpus luteum. However, excessive generation of ROS can lead to OS in ovarian cells and may contribute to ovarian-related diseases, particularly ovarian cancer [ 227 , 228 ].Under non-inflammatory conditions, ROS play a vital role in regulating cell signaling pathways and maintaining homeostasis. Inflammation is the initial step of the host’s immune defense against various harmful stimuli; it is a mechanism of innate immunity with a key role in immunosurveillance [ 226 ]. The inflammation process begins when immune cell receptors, including pattern recognition receptors (PRRs) and PAMPs, detect infectious components of pathogens. Activation of these PRRs triggers the activity of NF-κB as a major transcription factor. NF-κB promotes the release of inflammatory cytokines and ROS [ 229 ]. Chronic inflammation accounts for roughly 25% of human cancers. It produces ROS in inflammatory and epithelial cells, which can damage DNA and lead to mutagenic lesions and tumor formation [ 230 ]. Viral infections can elevate ROS, disrupting the redox balance. Human papillomaviruses (HPVs) are among the viruses that significantly promote oxidative stress (OS) [ 231 ]. During infection, HPV inserts its genetic material into the host cell’s DNA and recruits the cell’s metabolic processes to produce oncoproteins. These oncoproteins are associated with immune responses, inflammation, excessive ROS production, and ultimately oxidative damage [ 232 ]. The virus can create a chronic inflammatory microenvironment through IL-1β and IL-6, attracting immune cells to the lesion site. HPV can induce OS in the TME of HPV-related cancers. Additionally, it interferes with various components of antioxidant and DNA repair mechanisms to facilitate HPV DNA integration, viral replication, and assembly. Therefore, DNA damage has a significant role in the development of HPV-related cancers and can lead to genomic instability [ 233 ]. For example, in cervical cancer, the oncoproteins E5, E6, and E7 contribute to chronic inflammation, ROS production, and cancer progression. E6 has been shown to decrease levels of the main intracellular antioxidants glutathione (GSH) and catalase (CAT), along with their enzymatic activities, resulting in increased ROS production and DNA damage [ 226 ]. Briefly, HPV-induced inflammation causes ROS production, which damages host and viral DNA and leads to double-strand breaks. These damages allow HPV DNA to integrate into the host cell genome. Viral DNA integration results in the overexpression of E6 and E7 oncoproteins, which inactivate tumor suppressors and increase the transformation of cells into cancer. Another facet of HPV-related tumor development is EMT. EMT is a biological process defined as the trans differentiation of epithelial cells into mesenchymal cells. EMT generates epithelial cancer cells with tumor characteristics through various ways, such as enhanced cell motility, uncontrolled proliferation, invasion, and metastasis. Collectively, these changes promote cancer development. Inflammatory mediators in the tumor microenvironment, such as cytokines and chemokines, can induce EMT in cancer cells [ 230 , 234 ]. It was reported that Inflammatory cytokines can cooperate with the E6 and E7 oncoproteins and trigger the EMT in HPV-derived cancer, leading to their proliferation, growth, invasiveness, and survival [ 235 ].

Human papillomavirus (HPV), historically associated with cervical and other anogenital cancers, has emerged as a possible etiological factor in a subset of ovarian carcinomas, particularly in populations with high HPV prevalence [ 283 ]. This connection becomes more compelling when considering the profound role of chronic inflammation in shaping the ovarian tumor microenvironment. As reviewed, persistent HPV infection may hijack inflammatory signaling cascades, particularly via the activation of proinflammatory cytokines, chemokines, and innate immune sensors like inflammasomes and pattern recognition receptors (PRRs) to drive cellular transformation, immune escape, and tumor progression [ 129 ]. HPV’s oncogenic proteins, E6 and E7, not only disrupt tumor suppressors like p53 and Rb, but also exacerbate the inflammatory milieu by inducing NF-κB and STAT3 signaling, fostering sustained cytokine production (e.g., IL-6, IL-8, TNF-α and enhancing recruitment of immunosuppressive cells such as Tregs and M2 macrophages [ 93 ]. These changes undermine antitumor immunity and facilitate the establishment of a pro-tumorigenic niche. Moreover, the interplay between inflammatory pathways and hormonal signaling in ovarian tissues, such as estrogen-induced proliferation and cytokine synergy, further amplifies malignant potential [ 129 ]. Another pivotal element is oxidative stress, frequently driven by chronic inflammation and HPV-induced mitochondrial dysfunction. The resulting DNA damage and subsequent EMT contribute to tumor heterogeneity, metastasis, and resistance to therapy. Emerging evidence also highlights the role of inflammasome dysregulation (e.g., NLRP3, AIM2) in modulating both inflammation and cancer cell survival in the ovarian milieu [ 284 ]. Therapeutically, this molecular understanding has opened several avenues. Checkpoint inhibitors and therapeutic vaccines targeting HPV antigens show promise in reinvigorating immune responses, while NSAIDs and cytokine blockers (e.g., IL-6 or IL-1β antagonists) may reduce tumor-promoting inflammation [ 285 ]. Novel strategies such as CRISPR-Cas9 gene editing and epigenetic modulators offer precision tools to silence HPV oncogenes and reset aberrant inflammatory circuits. Nevertheless, translating these approaches to clinical practice faces challenges, including tumor heterogeneity, immune resistance mechanisms, and lack of robust biomarkers [ 268 ]. In conclusion, the intersection of HPV-driven inflammation and ovarian tumorigenesis represents a complex but potentially targetable network. Future research should focus on longitudinal studies to confirm causality, identify predictive biomarkers of inflammation-driven HPV-positive ovarian cancer, and refine combinatory therapeutic regimens [ 286 ]. A multidisciplinary approach integrating virology, immunology, oncology, and systems biology is essential to fully harness these insights and translate them into effective interventions that improve survival and quality of life for women with ovarian cancer.

The inflammatory TME in ovarian cancer significantly drives tumor progression, therapy resistance, and metastasis. Key pro-inflammatory mediators—such as IL‑6, TNF‑α, and COX‑2—activate survival pathways (e.g., JAK/STAT, NF‑κB) promoting proliferation, angiogenesis, and immune evasion. Therefore, therapeutic targeting of these inflammatory pathways has emerged as a promising strategy to inhibit tumor growth and enhance treatment outcomes [ 236 ]. Targeting inflammatory pathways in ovarian cancer involves disrupting signaling molecules and pathways that promote tumor growth, survival, and resistance to treatment. This approach aims to modulate the tumor microenvironment and enhance the effectiveness of other therapies like chemotherapy and immunotherapy [ 237 ]. In the following sections, we explore current therapeutic strategies that aim to target inflammation in ovarian cancer. Recent trials and preclinical studies demonstrate that modulating the immune system by targeting inflammation-related immunosuppressive pathways can enhance therapeutic efficacy in ovarian cancer [ 238 ]. Ovarian tumors typically exhibit an immunosuppressive TME dominated by regulatory T cells, M2-polarized macrophages, low TIL infiltration, and elevated levels of IL‑6, IL‑8, and TNF-α, fostering resistance to therapies [ 239 ]. The use of immune checkpoint inhibitors (ICIs), such as anti-PD‑1/PD-L1 (e.g., pembrolizumab, nivolumab) and anti-CTLA‑4 agents, aims to reinvigorate cytotoxic T cell responses by blocking inhibitory signals on T cells or antigen-presenting cells [ 240 ]. Clinical response rates to ICIs alone in ovarian cancer remain modest, typically 10–15% in patients with advanced disease. Reasons include low tumor mutational burden and limited T cell infiltration [ 241 , 242 ]. Emerging strategies focus on combination therapies, particularly pairing ICIs with anti-angiogenic agents (e.g., bevacizumab), PARP inhibitors (e.g., olaparib, niraparib), or cytokine modulators, to convert ‘cold’ tumors into ‘hot’ and boost immune activity [ 243 , 244 ]. Vaccination strategies targeting tumor-associated antigens (TAAs), such as New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and mucin-1 (MUC1), have shown promising potential in ovarian cancer immunotherapy. NY-ESO-1 is a cancer-testis antigen expressed in approximately 40% of epithelial ovarian cancers, and vaccination with NY-ESO-1 peptides has been demonstrated to elicit both CD8⁺ cytotoxic and CD4⁺ helper T cell responses in early-phase clinical trials [ 245 , 246 ]. One example is the CDX-1401 vaccine combined with the TLR3 agonist poly-ICLC and the IDO1 inhibitor, which demonstrated robust immunogenicity and potential clinical benefit in patients with recurrent ovarian cancer. Likewise, MUC1, a glycoprotein overexpressed and aberrantly glycosylated in ovarian tumors, has been targeted by novel vaccine formulations. A recent preclinical study reported that a MUC1-based vaccine, when co-administered with a PD-L1 checkpoint inhibitor, significantly boosted tumor-specific CD8⁺ T cell activation and suppressed tumor growth more effectively than monotherapies [ 247 ]. These findings support the rationale for combining cancer vaccines with immune checkpoint blockade to overcome the immunosuppressive tumor microenvironment and generate durable anti-tumor responses [ 248 ]. Recent advances in immunotherapy have explored the potential of engineered cytokine fusion proteins to reinvigorate exhausted T cells within the tumor microenvironment. One such strategy involves the development of Fc–IL‑4, a fusion of the Fc domain of IgG2a and interleukin‑4 (IL‑4), which selectively targets terminally exhausted CD8⁺ tumor-infiltrating lymphocytes (TILs) [ 249 ]. In a 2024 preclinical study, Feng et al. demonstrated that Fc–IL‑4 reprograms the metabolic state of these dysfunctional T cells by activating the STAT6 and PI3K–AKT–mTOR signaling axis, leading to increased glycolysis, mitochondrial fitness, and effector function [ 249 ]. When combined with immune checkpoint inhibitors or adoptive T cell therapy, Fc–IL‑4 significantly enhanced anti-tumor responses and led to durable tumor regression in murine models of solid tumors. Notably, pharmacological inhibition of STAT6 or mTOR abrogated the therapeutic effects, underscoring the pivotal role of metabolic reprogramming in T cell-mediated immunity [ 249 ]. These findings highlight Fc–IL‑4 as a promising adjunct to checkpoint blockade in overcoming immunosuppression within the tumor microenvironment [ 249 ]. Overall, immunomodulatory strategies targeting inflammatory pathways represent a promising frontier, but require biomarker-driven patient selection and combination [ 250 ]. Targeting pro-inflammatory mediators using pharmacological agents offers a promising strategy to mitigate ovarian tumor progression and overcome therapeutic resistance. Two major categories under investigation are non-steroidal anti-inflammatory drugs (NSAIDs) and cytokine blockers, particularly those targeting IL-6 signaling [ 129 ]. Chronic inflammation in the ovarian tumor microenvironment is characterized by upregulated cyclooxygenase-2 (COX-2) and prostaglandins, which support tumor growth, immunosuppression, angiogenesis, and metastasis [ 237 ]. Recent preclinical studies have focused on the anticancer properties of NSAIDs. In an ovarian cancer xenograft model, administration of sulindac (7.5 mg/kg/day for four weeks) led to approximately 70% reduction in tumor volume. Treated tumors displayed decreased COX-2 expression, reduced NF-κB activation, diminished IL-10 and TNF-α levels, and increased apoptosis, underscoring the compound’s anti-inflammatory and anti-tumor potential [ 236 ]. Similar efficacy has been observed with celecoxib and aspirin in vitro, demonstrating COX-2 inhibition, reduced matrix metalloproteinase (MMP) activity, and impaired cancer cell invasion and migration [ 251 , 252 ]. Although most NSAID-driven studies remain at preclinical stages, they suggest that COX-2 inhibition alone or in combination with chemotherapy or immunotherapy can reverse aspects of the inflamed, immunosuppressive microenvironment. Careful attention to dosing is critical due to the known side effects of chronic NSAID use [ 253 , 254 ]. The IL-6 signaling pathway is one of the central drivers of inflammation-mediated ovarian cancer progression. Elevated IL-6 levels in tumor tissue and patient serum correlate with increased STAT3 activation, chemotherapy resistance, angiogenesis, and poor prognosis [ 133 ]. Two IL-6 pathway inhibitors—siltuximab (anti–IL-6) and tocilizumab (anti–IL-6R)—have been evaluated. In ovarian cancer cell lines and xenograft models, siltuximab significantly reduced STAT3 phosphorylation, downregulated anti-apoptotic proteins (MCL-1, Bcl-xL, survivin), and enhanced paclitaxel sensitivity in vitro. However, its effect on tumor growth in vivo was modest [ 255 , 256 ]. In a phase II single-arm clinical trial involving platinum-resistant ovarian cancer patients, siltuximab was tolerable but showed limited efficacy; stable disease was observed in a subset, yet objective responses were lacking [ 257 ]. Tocilizumab has been tested in a phase I trial combined with carboplatin/doxorubicin and Peg-IFN-α2b. The regimen was safe and induced an immunological shift: decreased pSTAT3 levels, increased IL-12 and IL-1β production by myeloid cells, enhanced T cell activation, and more robust effector cytokine secretion, with several patients achieving objective responses or disease stabilization [ 255 ]. Additionally, preclinical studies on clear cell ovarian carcinoma demonstrated that blocking IL-6R via tocilizumab or siRNA diminished invasion and partially restored chemosensitivity [ 258 ]. Hemmat et al. (2022) showed siRNA suppression of HPV16 E5 in CaSki cells curtailed EGFR signaling and proliferation, a strategy extensible to OC [ 259 ]. Evidence suggests that solely targeting IL-6 signaling may not suffice due to tumor redundancy and compensatory pathways. Thus, ongoing efforts focus on combination approaches: pairing NSAIDs or cytokine blockers with chemotherapy, targeted therapy, epigenetic modulation, or immunotherapy to maximize antitumor efficacy [ 260 , 261 ]. NSAIDs have been tested alongside paclitaxel and checkpoint inhibitors to potentiate apoptosis and suppress MMP-mediated invasion [ 129 ]. Siltuximab and tocilizumab are being assessed in conjunction with hypomethylating agents, PARP inhibitors, or checkpoint blockade to overcome chemotherapy resistance and immune suppression [ 262 ]. CRISPR (clustered regularly interspaced short palindromic repeats) has revolutionized the field of medicine. CRISPR uses an endonuclease (Cas9) to cut DNA double strands and a small guide RNA (sgRNA) to identify target genomic sequences. The Cas9/sgRNA complex creates double-strand breaks (DSBs) and activates non-homologous end joining (NHEJ) or homologous recombination repair (HRR) to facilitate DNA repair. The CRISPR/Cas9 technique enables researchers to identify and investigate cancer-associated genes as potential therapeutic targets [ 263 – 265 ]. CRISPR plays a crucial role in treating ovarian cancer by editing the genome of cancer cells and the patient’s immune cells. This technology can slow tumor growth and promote cancer cell death by deleting or altering specific genes. In the treatment of ovarian cancer with CRISPR, one of the key effects is the removal of genes that support cancer cell growth and survival; for example, a study demonstrated that deleting the LINC00511 gene with CRISPR-Cas9 in an ovarian cancer cell line decreased cell proliferation and improved apoptosis [ 266 ]. In HPV-derived cancer, E6 and E7 oncoproteins have been considered as specific targets in gene therapy. Using CRISPR-Cas9 for gene therapy of HPV-derived cancer attributes E6 and E7 downregulations, leading to inactivation of p53 and RB to induce apoptosis and cell death [ 267 , 268 ]. The first application of CRISPR-Cas9 technology for featuring HPV16-E7 single-guide RNA (gRNA) was reported in 2014. Targeting the E7 genes of the HPV induces cell death in the HPV-driven cancer cells [ 269 ]. In a study, T. Yoshiba et al. developed a CRISPR-Cas9 approach using an AAV vector as a specific therapeutic system for targeting the E6 oncoprotein in cervical cancer. In this study, they used AAV type 2 with 5 kb packaging capacity as the vector, then constructed the sgRNA-expressing AAV vector to target E6. Transduction of AAV-sgE6 into Cas9-expressing cervical cancer cells resulted in multiple mutations in E6, enhanced expression of p53, and subsequently induced cell death in cervical cancer cells. Therefore, the results of this study presented that targeting E6 expression with CRISPR-Cas9 may be a promising and effective strategy in the treatment of cervical cancer [ 270 ]. Recognition of dsDNA with the CRISPR/Cas9 requires the tNGG PAM sequence in the target DNA strands, which are less common in genomic sequences. Because of this exceptional DNA targeting ability, the CRISPR/Cas9 system can be utilized as a biosensor for the detection of pathogens. For instance, H Vu Nguyen developed an NAA-free electrochemical biosensor using the CRISPR-Cas9 system to detect the presence of HPV 16 and HPV 18 L1 genes. This biosensor functions through a two-step detection process: First, the CRISPR/Cas9-single guided RNA (sgRNA) cleavage is activated by the Probe 1 (P1)-L1 duplex. This results in the production of cleaved fragments tagged with redox markers, specifically Methylene Blue (MB) or Ferrocene (Fc). The quantity of these labeled fragments corresponds directly to the amount of L1 targets present in the sample. In the second step, the electrochemical signals generated by the redox-labeled fragments, which hybridize with capture Probe 2 (P2) fixed on the sensing surface, are analyzed. Consequently, the biosensor is capable of detecting L116 and L118 genes across a broad concentration range from 1 fM to 10 nM, demonstrating high sensitivity with detection limits of 0.4 fM for L116 and 0.51 fM for L118 genes [ 271 ]. The current therapeutic approaches to target inflammatory pathways in ovarian cancer are summarized in Table 3 . Table 3 Therapeutic targeting of inflammatory pathways in ovarian cancer Strategy Key Agents Key Outcomes References Checkpoint Inhibition Nivolumab, Ipilimumab Enhances T-cell infiltration; 10–15% response rates in combination regimens [ 240 – 244 ] Cancer Vaccines NY-ESO-1 peptides, MUC1 formulations Induces CD8⁺ T-cell responses; attenuates tumor progression [ 245 – 248 ] Engineered Cytokine Fusion Fc-IL-4 fusion protein Reprograms exhausted TILs; augments anti-tumor efficacy [ 249 ] NSAIDs (COX-2 Inhibition) Celecoxib, Sulindac Reduces tumor volume by ~ 70%; promotes apoptosis via NF-κB downregulation [ 236 , 251 – 254 ] Cytokine Blockade Tocilizumab, Siltuximab Suppresses STAT3 signaling; restores chemosensitivity [ 255 – 258 , 260 – 262 , 272 ] CRISPR Gene Editing CRISPR-Cas9/sgRNA Disrupts oncogenes (e.g., HPV E6/E7); induces p53/RB-mediated apoptosis [ 263 – 270 ] CRISPR Biosensors Cas9-based electrochemical sensor Enables ultrasensitive HPV detection (LOD: 0.4–0.5 fM) [ 271 ] Therapeutic targeting of inflammatory pathways in ovarian cancer Despite substantial progress in understanding HPV-driven inflammatory pathways in ovarian carcinogenesis, several critical gaps persist that impede translation into effective therapies. Frontier research reveals that pro-inflammatory ascitic fluid and HPV-mediated modulation of the TME significantly contribute to immune evasion and metastasis in ovarian cancer [ 79 ]. Yet key challenges remain, particularly in linking HPV’s molecular actions to clinical endpoints. While HPV’s oncogenic roles are well-established in cervical cancer, its incidence, viral load dynamics, and integration status in ovarian tumors remain controversial and understudied [ 273 ]. HPV integration can alter viral gene expression and host genome regulation, affecting immune escape and inflammation. Expanding in-depth genomic profiling, including long-read sequencing of ovarian tumor samples is essential to clarify these mechanisms [ 274 ]. Furthermore, proinflammatory cytokines (e.g., IL‑6, TNF‑α), chemokines, inflammasome components, and pattern recognition receptors (like TLR9) have been implicated in HPV-associated TME remodeling. However, clinical biomarkers reliably reflecting the TME switch from protumor to antitumor remain elusive [ 275 ]. It is crucial to develop longitudinal biomarker panels, including circulating cytokines, immune cell phenotypes, and CpG methylation marks, to guide patient stratification and monitor therapeutic responses [ 276 ]. Another major challenge is that single-agent immune modulators have produced limited success in ovarian cancer [ 277 ]. Preclinical and early-phase clinical data show that combining anti-inflammatory agents such as NSAIDs or IL‑6/IL‑6R blockers with immunotherapies or epigenetic drugs can reshape the TME. The challenge now lies in optimizing dosing regimens, sequencing, and identifying synergistic drug combinations while managing toxicity [ 278 ]. Adaptive umbrella trial designs provide promising platforms for multitarget testing. Moreover, the epigenetic immune interface in HPV-driven cancer is gaining attention. HPV oncogenes E6 and E7 drive epigenetic changes that suppress innate antiviral signaling such as interferon-kappa (IFN‑κ) silencing, promote immune escape, and sustain inflammatory loops [ 279 ]. Leveraging epigenetic modulators such as DNA hypomethylating agents to restore antiviral responses and reprogram the TME in HPV-associated ovarian cancer is a compelling but underexplored avenue [ 280 ]. Heterogeneous ovarian tumors require personalized analysis, and the integration of transcriptomic, epigenomic, and proteomic data has enabled the identification of tailored treatments such as targeting MAPK/PI3K pathways in preclinical settings [ 281 ]. Incorporating inflammatory signature profiles within artificial intelligence-enabled platforms will be critical to predict responses to HPV-targeted and anti-inflammatory therapies [ 238 ]. Bridging HPV-driven inflammation to clinical practice demands a multidisciplinary strategy, including high-resolution viral-genomic characterization, validated TME biomarker assays, iterative translational trials, epigenetic reprogramming, and AI-informed combinatorial regimens. Achieving this paradigm could unlock new immunotherapeutic frontiers in preventing or treating HPV-associated ovarian cancer [ 282 ].

Inflammation, derived from the Latin expression “to set on fire,” is a biological response that may present in acute or chronic forms. Its activation is influenced by diverse lifestyle factors, including alcohol consumption, pathogenic infections, obesity, and exposure to ionizing radiation, psychological stress, tobacco use, and various environmental toxicants. Beyond these external determinants, endocrine fluctuations involving sex hormones such as estrogen, progesterone, and testosterone are also implicated in initiating inflammatory processes. Importantly, lifestyle-associated exposures modulate the biosynthesis of inflammatory mediators and enhance the generation of ROS, thereby amplifying the inflammatory response. ROS serve as critical molecular effectors by orchestrating the expression of chemokines, cytokines, cyclooxygenase-2, and transcription factors with proinflammatory activity [ 30 ]. Inflammation represents a protective response to tissue damage or external insult and constitutes a fundamental component of innate immunity. Nevertheless, persistent or chronic inflammation has been strongly associated with tumor initiation and progression. Emerging evidence underscores the pivotal contribution of inflammation to carcinogenesis, particularly through the activity of innate immune cells such as macrophages, which promote malignant transformation and tumor progression by secreting proinflammatory mediators, including TNF-α and IL-6 [ 31 ]. Acute inflammation is a rapid and short-term response to tissue injury or infection, which is associated with the activation of innate immune cells such as neutrophils and macrophages. This type of inflammation usually leads to the clearance of injurious agents and the initiation of the repair process, and in some cases can enhance antitumor responses [ 32 ]. In contrast, chronic inflammation, which persists for a long time in the body, is often accompanied by the continuous release of cytokines, reactive ROS, and enzymes such as COX-2. These factors can cause DNA damage, genomic instability, and stimulation of angiogenesis, conditions that favor the growth and survival of cancer cells [ 33 ]. The inflammatory response serves primarily to restore tissue homeostasis, either by removing damaged cells or initiating repair mechanisms. In the acute phase, vascular changes near the site of injury enhance blood flow, which is followed by the activation of resident innate immune cells—including macrophages, dendritic cells, and mast cells—and the recruitment of additional innate immune cells to the affected area. Inflamed tissues exhibit elevated levels of ROS, cytokines, chemokines, and growth factors, produced by both immune and tissue-resident cells. This acute response is essential for protecting tissue integrity and maintaining homeostasis in the face of routine microbial or environmental challenges. However, when inflammation is unresolved or repeatedly triggered, it can evolve into chronic inflammation, a process closely linked to the initiation and progression of EOC [ 34 ]. Macrophages and T lymphocytes can release tumor TNF-α and macrophage migration inhibitory factor, which may exacerbate DNA damage [ 35 ]. As a result, the TME is composed of a complex mixture of cells, including innate immune populations such as macrophages, neutrophils, mast cells, myeloid-derived suppressor cells, dendritic cells, and natural killer cells, as well as adaptive immune cells like T and B lymphocytes, alongside cancer cells and their surrounding stroma, which consists of fibroblasts, endothelial cells, pericytes, and mesenchymal cells. Among these, tumor-associated macrophages (TAMs) and T cells are the most prevalent, with TAMs largely promoting tumor growth and playing essential roles in angiogenesis, invasion, and metastasis [ 36 ]. Inflammation is closely linked to both the onset and progression of multiple cancer types, including EOC and its high-grade serous subtype (HGSC). Notably, EOC is associated with inflammation triggered by ovulation and peritoneal irritation, and this inflammatory environment contributes to tumor progression. At sites of inflammation, epithelial cells are exposed to increased levels of ROS, cytokines, prostaglandins, and growth factors, which collectively drive enhanced cell proliferation, as well as genetic and epigenetic changes. These alterations promote malignant transformation, tumor growth, and survival. Furthermore, the proinflammatory TME plays a critical role in facilitating metastasis and resistance to chemotherapy in EOC. This narrative review will explore the multifaceted roles of inflammation and inflammatory mediators in EOC initiation, progression, metastasis, and chemoresistance [ 34 ]. Chronic inflammation is a sustained and dysregulated immune response that persists beyond the resolution phase of acute inflammation, characterized by continuous immune cell infiltration, prolonged cytokine production, and progressive tissue remodeling. In cancer biology, chronic inflammation plays a central role in tumor initiation, promotion, and immune evasion. Unlike the neutrophil-dominated response of acute inflammation, chronic inflammation is marked by the infiltration of mononuclear leukocytes—primarily macrophages, lymphocytes, and plasma cells—into the TME. These cells secrete a persistent pro-inflammatory cytokine milieu, including IL-6, TNF-α, IL-1β, and transforming growth factor-beta (TGF-β), which collectively promote angiogenesis, epithelial-to-mesenchymal transition (EMT), and immunosuppression [ 37 , 38 ]. Chronic inflammation is sustained by the constitutive activation of key signaling pathways such as NF-κB, JAK/STAT, p38 MAPK, COX-2, ERK, mTOR, and AP-1, which drive transcription of genes involved in inflammation, survival, and proliferation [ 39 ]. Additional modulators such as FOXO1/3, KEAP1, and TRAF2 regulate oxidative stress responses and immune cell survival, further reinforcing the inflammatory state [ 37 ]. T cells within chronically inflamed tumors frequently exhibit exhaustion, marked by sustained expression of immune checkpoint molecules such as PD-1, CTLA-4, and LAG-3. These inhibitory receptors are upregulated in response to persistent antigen stimulation and inflammatory cytokines, leading to impaired cytotoxic function and reduced tumor clearance [ 40 ]. Simultaneously, regulatory T cells (Tregs) expand and suppress effector T cell responses, further dampening anti-tumor immunity [ 41 , 42 ]. B cells and plasma cells contribute to chronic inflammation by producing autoantibodies and cytokines that modulate the TME, while myeloid-derived suppressor cells (MDSCs) inhibit T cell activation and promote tumor tolerance through arginase-1 and ROS production [ 43 – 45 ]. Chronic infections such as HPV and H. pylori further exacerbate immune activation and contribute to oncogenesis [ 46 , 47 ]. The pathological consequences of chronic inflammation in cancer are profound: persistent cytokine signaling enhances tumor cell proliferation and survival, while upregulation of immune checkpoint molecules like PD-L1 suppresses cytotoxic T cell responses, facilitating immune evasion [ 48 ]. Moreover, inflammatory mediators such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) promote angiogenesis and metastasis, while activated fibroblasts and myofibroblasts deposit extracellular matrix components that support tumor progression and fibrosis [ 49 , 50 ]. The activation of several transcription factors, including NF-κB, STAT, and FOXO, is brought on by the stimulation of intracellular signaling pathways that are triggered by pattern recognition receptors (PRRs) contact. These variables control the expression of several genes related to both adaptive and innate immunity. Chronic inflammation can encourage carcinogenesis and can be caused by prolonged inflammatory signaling, recurrent tissue damage, inadequate pathogen clearance, and failure of anti-inflammatory systems [ 51 ]. HPV disrupts the immune response in keratinocytes by affecting the function of TLR3, PKR, MDA5, and RIG-I. Additionally, the transcription of chemotactic and proinflammatory genes in HPV-infected skin cells is suppressed [ 52 ]. Dendritic cells (DCs), especially Langerhans cells (LCs), are critical for immune surveillance in HPV infection, as they reside in the epithelium and can present viral antigens to T cells after migrating to lymph nodes. However, HPV impairs this process through various mechanisms. The virus does not replicate in LCs and downregulates MHC-I expression in infected epithelial cells, leading to poor T cell activation. Upon infection, keratinocytes release pro-inflammatory cytokines that recruit and activate LCs. Yet, they also produce anti-inflammatory molecules like IL-1dc0 and TGF-β, especially during tumor development, which suppresses LC function. Additionally, HPV proteins E6 and E7 suppress TLR9 signaling and IFN production, enhancing immune evasion. In contrast, TLR4 is overexpressed in infected cells and is linked to apoptosis resistance [ 53 ]. Neutrophils are produced by the bone marrow and are essential for the body’s defense against acute inflammation and infections. Their short lifespan and segmented nucleus set them apart [ 54 ]. In carcinogenesis, neutrophils play a dualistic role by either encouraging or preventing the development of tumors. The complex functions of neutrophils as regulators in this process have been demonstrated by recent research. This adaptability is crucial when considering the TME. Neutrophils are divided into N1 (anti-tumor) or N2 (tumor-promoting) groups depending on the context. N2 neutrophils cause ROS production, angiogenesis, and increased genetic instability. They can also inhibit the function of natural killer (NK) and T cells by producing PGE2, which contributes to immune evasion [ 54 ]. The first cells to migrate during the early stages of inflammation are neutrophils, which are controlled by mast cells and macrophages in the tissues. A signaling network comprising cytokines, chemokines, and growth factors for defensive action against infection activates and recruits different types of leucocytes, most of which are macrophages and lymphocytes, to the inflammatory site at a later stage of inflammation. Classically activated neutrophils with the N1 phenotype have antitumor properties. By producing inflammatory mediators that are lethal to tumor cells, such as TNF-Alfa, MIP-1 ALFA, H2O2, and NO, chemokines like CXCL8, CXCL1, CXCL2, and CXCL3 attract it to the tumor microenvironment [ 55 ]. Additionally, neutrophils aid in the process of tumor cell proliferation, survival, extravasation, and tissue invasion at secondary locations. Immature myeloid cells and Treg cells are among the other cells in the TME that promote dissemination. These cells effectively suppress the adaptive immune system’s reaction to tumor growth. In addition to providing a framework for the tumor tissue, cancer-associated fibroblasts also interact with cancer cells and control immunity. Lastly, platelets have an impact on inflammation, thrombosis, and tumor cell survival. To sum up, the TME has a range of immunocompetent cells that promote metastasis and dissemination [ 56 ]. TAMs are derived from blood monocytes and are polarized into either M1 (anti-tumor) or M2 (tumor-promoting) phenotypes. TAMs constitute approximately half of tumor masses and may function as M1 in early stages, but as the tumor progresses, they convert to M2 to support growth, angiogenesis, and metastasis [ 57 ]. TME is believed to significantly influence the advancement of ovarian cancer. A key element of the TME consists of TAMs. Macrophages are generally classified into two categories based on their secreted cytokines and chemokines: M1 pro-inflammatory and M2 anti-inflammatory. Within the context of the TME, macrophages predominantly exhibit an M2 phenotype, which dampens the immune environment, aids tumor cells in dodging immune detection, and promotes tumor development and spread. In contrast, M1 macrophages contribute to an immune response against tumors and correlate with a better prognosis in solid tumors. An increased presence of M2-type TAMs is recognized as a characteristic sign of poor prognosis in ovarian cancer [ 58 ]. In addition, they secrete proinflammatory cytokines such as IL-10, TGF-β, and VEGF and degrade the extracellular matrix, which promotes tumor progression [ 57 ]. Inflammation is widely recognized as a key driver of tumor initiation and progression, yet emerging evidence reveals that certain inflammatory mediators, notably IL-37 and IL-24, paradoxically suppress malignancy by orchestrating anti-tumor immune responses, inhibiting angiogenesis, and inducing apoptosis. Indeed, IL-37, a dual-function member of the IL-1 cytokine family, is synthesized as a precursor that, upon caspase-1 cleavage, forms a complex with Smad3 which translocates to the nucleus to downregulate inflammatory genes including IL-1β, IL-6, TNF-α, and IFN-γ. Extracellularly, IL-37 binds IL-18Rα and recruits IL-1R8 (SIGIRR), thereby suppressing NF-κB and MAPK pathways while activating negative regulators such as PTEN and DOK1 [ 59 ]. As a result, IL-37 inhibits tumor angiogenesis by reducing VEGF, HIF-1α, and Ang-2 expression, and restricts metastasis by preventing pro-migratory signaling. This cytokine also repolarizes tumor-associated macrophages from the pro-tumor M2 phenotype to anti-tumor M1, boosts NK and CD8⁺ T cell infiltration, and blocks immunoregulatory checkpoints PD-1 and TIM-3, effectively revitalizing anti-tumor immunity within the tumor microenvironment [ 60 – 62 ]. Notably, IL-37 enhances NK cell cytotoxicity via ERK and NF-κB signaling and accelerates IL-1R8 degradation, correlating with improved patient survival in colon, lung, and skin cancers. Clinical studies consistently show that higher intra-tumoral or serum concentrations of IL-37 are inversely related to tumor stage and directly linked to prolonged survival, underscoring its potential utility as both a prognostic indicator and therapeutic target [ 63 , 64 ]. Similarly, IL-24—originally identified as melanoma differentiation-associated gene-7 (MDA-7)—is a member of the IL-10 cytokine family distinguished by its potent, tumor-selective antitumor activity. Upon overexpression via adenoviral vectors such as Ad.mda-7, IL-24 accumulates in the ER/Golgi of cancer cells, triggering ER stress, ROS generation, ceramide production, and activation of pro-apoptotic pathways including p-eIF2α, ATF4, Bax/Bak, Fas/FasL, and tumor suppressors such as SARI or AIF [ 65 ]. Extensive preclinical studies demonstrate that IL-24 induces apoptosis or toxic autophagy in multiple tumor types while sparing normal cells—a specificity attributed to differential ER stress responses and altered ROS handling in malignant cells [ 65 ]. Both IL-37 and IL-24 exert their anti-tumor functions by modulating key oncogenic signaling pathways. IL-37 inhibits NF-κB, MAPK, STAT3, and JAK/STAT via Smad3 and receptor-mediated signaling, consequently suppressing inflammatory and pro-survival programs [ 59 ]. In parallel, IL-24’s induction of ER stress and ROS cascades leads to mitochondrial dysfunction, autophagic death, suppression of Bcl-2 family proteins, and activation of death receptors, while inhibiting angiogenesis by downregulating VEGF and TGF-α and suppressing Src signaling. Moreover, IL-24 modulates immune engagement through enhancement of Th1 cytokines and potentiation of CD8⁺ T cell and NK cell responses [ 66 ]. Several malignant cells are known to constitutively release low levels of tumor necrosis factor-α (TNFα), a cytokine that plays a central role in sustaining inflammatory processes. Substantial evidence indicates that tumor-derived TNFα promotes the initiation and progression of diverse cancers, including those of the skin, ovary, pancreas, and gastrointestinal tract, whether syngeneic, xenogeneic, or chemically induced. Within the tumor microenvironment, however, TNFα is not solely produced by malignant cells; immune populations such as CD4⁺ lymphocytes and macrophages also contribute significantly, as shown in genetic models of liver cancer where their secretion of TNFα was pivotal in driving inflammation. In the context of epithelial ovarian cancer, TNFα fosters intricate crosstalk between tumor cells and the surrounding stromal tissues, thereby facilitating peritoneal colonization and advancing disease progression. Kulbe et al. demonstrated that rising levels of chemokines (CCL2, CXCL8, and CXCL12), IL-6, VEGF, and macrophage migration inhibitory factor-1 (MIF-1) were linked to constitutive production of TNFα. Through indirect effects on tumor cell survival and dissemination via CXCR4 and CXCR4/CXCL12, TNFα also stimulates the growth of new blood vessels in peritoneal tumor colonies by inducing the production of VEGF and CXCL12 [ 67 ].

One of the most common gynecological cancers, ovarian cancer (OC) has a high death rate because it is often detected late and recurs frequently. It is one of the most prevalent malignancies in women globally, and even with improvements in chemotherapy and surgery, the overall five-year survival rate is still around 50% and is the fifth most common cause of cancer-related deaths in women [ 1 , 2 ]. When gynecological tissues proliferate uncontrollably and develop into a malignant tumor, ovarian cancer arises [ 3 ]. Germ cell tumors, sex cord-stromal tumors, and epithelial ovarian cancer (EOC) are the three most prevalent forms of ovarian cancer, which is a diverse disease. Roughly 90% of all ovarian malignancies originate from the epithelium [ 4 ]. Thus, it is crucial to have a thorough understanding of the pathophysiological mechanisms underlying OC and to identify extrinsic risk factors that contribute to the development and spread of tumors [ 2 ]. One of the characteristics of cancer is inflammation, which is also widely regarded as one of the most significant environmental variables for carcinogenesis and tumor growth [ 3 ]. A significant risk factor for the development of EOC appears to be chronic inflammation, among other variables like genetics, environment, and lifestyle. Accelerated quantities of inflammatory mediators, including pro-inflammatory cytokines, chemokines, and hormones, are present in epithelial cells. These mediators cause oxidative stress, which damages DNA and leads to accelerated cell division, genetic alterations, and epigenetic modifications. Ovulation, infection, and endometriosis are the primary causes of inflammation in the fallopian tubes and ovaries. The most widely accepted theory of ovarian carcinogenesis suggests that ovarian rupture, inflammation, and continuous ovulation contribute to a pro-oxidative microenvironment and result in mutagenic DNA damage. This microenvironment not only promotes tumorigenesis but also facilitates the survival and proliferation of malignant cells. Consequently, understanding the interplay between inflammation and ovarian cancer development is crucial for identifying potential therapeutic targets and preventive strategies [ 4 ]. The term ovarian cancer primarily refers to a group of malignancies originating from the epithelial lining of the ovary, fallopian tube, or peritoneum—collectively classified as EOC Risk factors for EOC identified early on, such as parity, contraceptive use, ages of menarche and menopause, led researchers to propose incessant ovulation and gonadotropin hormone levels were the two major mechanisms by which ovarian carcinogenesis occurred. However, there has been accumulating epidemiologic evidence of risk factors associated with EOC that do not directly affect ovulation or hormones levels. These risk factors include use of body powder use, obesity, endometriosis, and tubal ligation, all of which are associated with local inflammation, leading Ness and Cottreau to propose the hypothesis of inflammation as a pathophysiologic contributor to EOC etiology [ 3 ]. Inflammatory processes can promote tumor development by inducing the release of pro-tumorigenic mediators such as cytokines—particularly interleukin-6 (IL-6) and interleukin-8 (IL-8)—as well as chemokines, reactive oxygen species (ROS), and lipid hydroperoxides. These mediators can trigger a cascade of molecular events, including DNA damage, genetic mutations, and epigenetic alterations, ultimately increasing the susceptibility of affected tissues to malignant transformation [ 5 ]. In fact, there are several cyclical processes necessary for ovulation that share commonalities with inflammatory responses such as the production of chemokines and cytokines, an influx of leukocytes to the microenvironment and rapid angiogenesis. Ovarian tumors possess a unique tumor microenvironment (TME) whose immunosuppressive features are associated with shorter overall survival rates. Emerging evidence suggests that chronic infection and inflammation contribute to approximately 25% of all cancer cases [ 3 ]. Numerous pieces of evidence seem to support the idea that viral infection and pathology are closely related, especially for certain HR-HPV genotypes (16 and 18 initially). This suggests that other viral infections, like cytomegalovirus (CMV), which is frequently linked to HPV, may also be present. This highlights the connection between infection and disease stage, with a higher percentage of viral presence as the illness progresses, clarifying its function in terms of both onset and prognosis [ 6 , 7 ]. It is believed that HPV oncogenes directly induce malignancies associated to the HPV [ 8 – 11 ]. Alternatively, HPV-induced chronic inflammations, which are also brought on by HPV oncogene activity, may potentially indirectly trigger various kinds of malignancies [ 12 ]. Recurrent tissue damage and the emergence of mutations in the essential tumor suppressor genes are linked to chronic inflammation. Thus, the development of HPV-induced malignancies is caused by the ongoing HPV infection and the chronic inflammation that goes along with it. Pro-inflammatory cytokine overexpression in HPV-positive patients may also be influenced by HPV oncogenes [ 13 , 14 ]. It is known that HPV oncoproteins (E5, E6, and E7) promote some inflammatory pathways in addition to their well-known targets, which include cellular tumor suppressors (p53 and pRB) and epidermal growth factor receptors (EGFR) [ 13 ]. In a recent study, it was reported that HR-HPV, along with CMV and Epstein–Barr virus (EBV), was detected in both fallopian tube tissues and ovarian tumors. The authors suggested that persistent HPV infection, particularly in the fallopian tube epithelium, may act as a cofactor in the initiation and progression of EOC. They further proposed that viral oncoproteins and chronic inflammation driven by infection could contribute to the malignant transformation of epithelial cells, supporting a potential etiological role for HR-HPV in ovarian carcinogenesis [ 15 ]. HR-HPV is a well-established etiological factor in cervical cancer and head and neck squamous cell carcinoma. The viral oncoproteins E6 and E7 encoded by HR-HPV can inactivate key tumor suppressor proteins, such as p53 and Rb, which may also contribute to the development of EOC. Given these oncogenic mechanisms, researchers have investigated the potential involvement of HPV in ovarian carcinogenesis. However, findings remain inconclusive, with some studies detecting HPV DNA in EOC samples, while others report no significant association [ 16 ]. A meta-analysis of 43 studies, including 19 case-control studies, reported a 10% overall prevalence of HPV in ovarian cancer tissues and 7% specifically for HPV types 16 and 18. The analysis showed a significant association between HPV 16/18 and increased ovarian cancer risk (OR: 4.92; 95% CI: 1.96–12.53) [ 16 ]. Viruses have evolved diverse mechanisms to evade host immune surveillance and circumvent antiviral responses. While they can act as cofactors and amplify the oncogenic potential of other pathogens, current evidence does not support a direct causal role for viruses in the development of ovarian cancer [ 17 ]. Complementing these findings, a global meta-analysis reported HPV positivity in 15.5% of OC patients (range: 0%–67%) [ 18 ]. Contemporary investigations lend further credence to this link. For example, Le et al. synthesized data from 19 case-control studies involving 1071 °C and 906 benign samples, yielding an HPV prevalence of 16.4% in OC cases versus 5.7% in controls (OR: 3.09; 95% CI: 1.85–5.17); notably, HPV-16 and HPV-18 subtypes conferred substantially higher risks (OR: 4.36 and 3.98, respectively). This meta-analysis excels in its rigorous subgroup analyses of high-risk genotypes, thereby bolstering the robustness of pooled estimates; nevertheless, the pronounced heterogeneity observed in random-effects modeling—potentially attributable to geographic and diagnostic disparities—calls for supplementary sensitivity analyses to sharpen interpretive precision [ 16 ]. Li et al. reported significantly higher HPV-18 and HPV-33 prevalence in 322 epithelial OC samples compared to benign and normal tissues, suggesting a role in tumorigenesis, especially with risk factors like family history. The use of direct sequencing in this study bolsters genotyping accuracy and mechanistic insights; nonetheless, reliance on paraffin-embedded tissues introduces risks of DNA degradation, potentially leading to false negatives in cases with low viral loads [ 19 ]. Fatima et al. detected HPV in 22.5% of 40 °C samples (predominantly HPV-16), corroborating an association in low-resource settings. By emphasizing genotyping in low- and middle-income contexts, this work underscores the relevance of HPV in underserved populations; yet, the modest sample size limits statistical power, particularly for HPV-18 subgroups, and restricts generalizability beyond regional cohorts [ 18 ]. Paradowska et al. identified HPV-16 DNA in 51.5% of 97 EOC cases (higher in high-grade serous OC; OR: 9.1; 95% CI: 1.7–169.2), alongside CMV/EBV, positioning chronic fallopian tube infection as a potential cofactor via p53/pRb inactivation. The integration of quantitative ddPCR and qPCR methods here allows precise viral load assessment, strengthening causal inferences; however, the single-center Polish cohort and wide confidence intervals highlight the need for multi-ethnic validation to address potential population-specific biases. However, conflicting evidence tempers enthusiasm for HPV as a primary etiological factor [ 15 ]. Ingerslev et al. detected high-risk HPV in only 0.5% of 198 EOC samples from Caucasian populations, arguing against a meaningful role and urging focus on other agents. This large-scale application of sensitive real-time PCR effectively minimizes false positives and provides a strong benchmark for low-prevalence scenarios; nevertheless, the exclusive focus on Caucasian participants may overlook elevated rates in high-prevalence regions such as Asia or Latin America, limiting broader applicability [ 20 ]. Farazaneh et al. found no HPV DNA in 105 °C specimens. By systematically ruling out HPV in an Iranian cohort, this study supports population-specific etiological models; however, the exclusive use of PCR may overlook integrated or low-copy viral DNA, as evidenced by the negative controls, potentially underestimating subtle contributions [ 21 ]. Konidaris et al. reported similar positivity rates in malignant (27.9%) and benign (45.2%) cases ( p = 0.2), with no significant difference. The direct malignant-benign comparison via in situ hybridization (ISH) offers valuable histopathological context; yet, ISH’s inherently lower sensitivity relative to PCR could underestimate true prevalence, particularly for non-integrated viral forms [ 22 ]. Serological data from Hisada et al. showed no elevated HPV-16 antibodies in 36 °C patients versus controls ( p = 0.9). The prospective design of this serological approach reduces selection bias and provides indirect exposure insights; however, the small OC subgroup and narrow focus on HPV-16 alone may neglect contributions from other genotypes, diluting overall discriminatory power [ 23 ]. Moreover, Capozzi et al.‘s meta-analysis (PRISMA-compliant) revealed no significant dysbiosis difference, including HPV, between OC (40.2%) and controls (31.2%; OR: 0.94; 95% CI: 0.61–1.47; p = 0.779), attributed to high heterogeneity (I²=76%). Incorporating a broad microbiome perspective beyond HPV enriches the ecological framework; nonetheless, treating HPV as a mere dysbiosis subset dilutes targeted analysis, with methodological heterogeneity from diverse sampling techniques confounding pooled interpretations [ 24 ]. Erkanli et al. found 37.5% prevalence in malignant EOC with p53 correlation ( r = 0.47; p = 0.001), yet no overall etiological significance (OR = 1.5; p = 0.4). The mechanistic linkage to p53 via immunohistochemistry advances understanding of viral-tumor suppressor interactions; however, the study’s older design, modest sample size ( n = 72), and reliance on ISH may miss non-integrated HPV, tempering etiological claims [ 25 ]. These discrepancies likely arise from methodological variations (e.g., PCR sensitivity, sample type, geographic cohorts) and underscore the need for standardized, large-scale studies to clarify HPV’s cofactor role in inflammation-driven OC. Despite these inconsistencies, the cumulative evidence positions HPV as a plausible enhancer of chronic inflammation in OC, warranting further mechanistic and translational research. Inflammation has emerged as a key contributor to the initiation and progression of ovarian cancer. Chronic inflammatory conditions such as ovulation, pelvic inflammatory disease (PID), endometriosis, polycystic ovary syndrome (PCOS), and obesity are recognized as major sources of inflammation in the ovarian and fallopian tube microenvironment. These conditions promote tissue damage, repair cycles, and immune cell infiltration, all of which create a pro-tumorigenic milieu conducive to malignant transformation. Persistent peritoneal inflammation activates multiple oncogenic signaling pathways and immune responses, significantly contributing to EOC development and chemoresistance [ 26 ]. Elevated levels of proinflammatory cytokines, such as IL-6, IL-8, and tumor necrosis factor-alpha (TNF-α), along with oxidative stress (OS) and the recruitment of immune cells, foster a tumor-promoting environment. These inflammatory mediators facilitate DNA damage, epigenetic dysregulation, and immune evasion, which together accelerate ovarian tumor progression [ 27 , 28 ], Globally, 15.5% (0%–67%) of OC patients were HPV-positive, according to a meta-analysis on the prevalence of HPV in OC [ 29 ]. The existence of HR-HPV genotypes in both the upper and lower genital tracts may indicate that HPV plays a role in the development of EOC. This narrative review aims to provide a critical exploration of the potential role of HR-HPV in the development of epithelial ovarian cancer, with particular emphasis on the interactions between chronic inflammation, viral oncogenes, and tumor-promoting molecular pathways. By synthesizing epidemiological evidence with mechanistic insights from both ovarian cancer and other HPV-associated malignancies, the review seeks to clarify whether HPV-driven inflammatory processes contribute to ovarian carcinogenesis. In addition, it discusses emerging therapeutic strategies designed to target inflammation, viral persistence, and immune evasion within the ovarian tumor microenvironment. Ultimately, the purpose of this work is to offer a comprehensive perspective on HPV-associated inflammatory mechanisms in ovarian cancer and to highlight for prevention and treatment.

The main feature of tissue inflammation is the activation and penetration of innate and adaptive immune cells. The first line of defense for the host is the innate immune system, which is triggered by danger signals such as metabolite-associated danger signals and pathogen- and danger-associated molecular patterns. Antigen-presenting cell (APC) activation-mediated adaptive immune responses or phagocytosis and production of physiologically active molecules are two ways that innate immunity activation can directly or indirectly contribute to tissue inflammation or immunological resolution. Innate cells not only directly participate in antitumor responses, but also facilitate immune evasion or tumor suppression by regulating Treg, Th, and CD8 + T cells. For example, M2-Macrophages and MDSCs impair antitumor immunity by suppressing CD8 + and stimulating Tregs [ 185 ]. Microorganisms that activate innate immune cells by PRR (PAMP: PRR recognition) produce pathogen-associated molecular patterns (PAMPs), which are danger signals. These mechanisms include TLR, nod-like receptors, and C-lectin receptors, which have a high affinity for facilitating the downstream signaling cascade to initiate immune responses [ 186 ]. PAMPs and damage-associated molecular patterns (DAMPs) are detected by PRRs, which are sensors in the immune system. By starting defense mechanisms against infections and preserving immunological homeostasis, they act as crucial connections between the innate and adaptive immune responses [ 187 ]. PRRs are used by antigen-presenting cells, including DCs, to identify PAMPs, which are particular molecular signatures on pathogens. PRRs activate antigen-presenting cells and trigger adaptive immunity when they recognize PAMPs [ 188 ]. Toll-like receptors, RIG-I-like receptors, NOD-like receptors, and C-type lectin receptors are examples of innate PRRs that mediate the first detection of infection. These PRRs initiate intracellular signaling cascades that result in the transcriptional expression of inflammatory mediators, which synchronize the removal of pathogens and infected cells [ 189 ]. The role of various PRRs in HPV-induced inflammation is summarized in Table 1 . Table 1 Pattern recognition receptors (PRRs) implicated in HPV-mediated inflammation PRR Family Receptor Recognized Ligand Cellular Localization Ref TLRs TLR9 CpG motifs in HPV DNA Endosome Triggers Type I IFNs, pro-inflammatory cytokines [ 190 ] TLR4 HPV L1 capsid protein (via tissue damage) Cell membrane Activates IL-6, TNF-α, IL-1β production [ 191 ] TLR3 dsRNA intermediates Endosome Induces IFN-β, antiviral state [ 191 ] NLRs NLRP3 DAMPs: ROS, ATP, K⁺ efflux Cytoplasm Forms inflammasome, releases IL-1β, IL-18 [ 192 ] ALRs AIM2 Cytosolic HPV DNA Cytoplasm Induces pyroptosis, IL-1β release [ 192 ] RLRs RIG-I dsRNA or structured RNA Cytoplasm May sense HPV transcripts; antiviral gene induction [ 192 ] cGAS-STING Pathway cGAS Cytosolic HPV DNA Cytoplasm Triggers IFN-β, pro-inflammatory cytokines [ 193 , 194 ] Pattern recognition receptors (PRRs) implicated in HPV-mediated inflammation A well-characterized family of PRRs, TLRs are essential for the early identification of harmful microbes. There are ten functional TLRs (TLR1–TLR10) known to exist in humans, while mice have twelve functional members (TLR1–TLR9 and TLR11–TLR13). The subcellular location of type I transmembrane glycoproteins, or TLRs, determines their classification. Whereas TLR3 and TLR7-TLR9 are found in intracellular endosomal compartments, where they detect nucleic acids of microbial origin, TLR1, TLR2, TLR4-TLR6, and TLR11 (in mice) are expressed at the cell surface and mainly recognize microbial membrane components. An intracellular Toll/interleukin-1 (IL-1) receptor (TIR) domain mediates signal transduction that triggers downstream inflammatory pathways, a single transmembrane domain, and an extracellular leucine-rich repeat domain that recognizes ligands are the conserved structural components shared by all TLRs [ 195 ]. TLRs are expressed across a broad range of cell types, extending beyond classical immune cells such as antigen-presenting cells (APCs) and NK cells to include non-immune populations like stromal, epithelial, and even malignant cells. TLR signaling is generally divided into two major pathways: the MyD88-dependent and the TRIF-dependent cascades. With the exception of TLR3, which signals exclusively through TRIF, most TLRs rely on the MyD88-dependent pathway. Notably, activation of TLR7 and TLR9 through this pathway induces type I interferon (IFN) responses, involving TRAF3 and IRF7. Upon phosphorylation, IRF7 migrates into the nucleus, where it drives the transcription of IFN-α and IFN-β. By contrast, TLR3 and TLR4 initiate the TRIF-dependent pathway, which promotes the production of proinflammatory cytokines and type I IFNs. TRIF activates NF-κB via two distinct mechanisms: its N-terminal region interacts with TRAF6, while the C-terminal domain engages RIP1, leading to TAK1 activation. Within this regulatory network, IRF7 serves as the key driver of IFN-α expression, whereas Interferon regulatory factor 3 (IRF3) is required for IFN-β synthesis. In particular, TLR3 signals through the TRIF-dependent cascade, where IRF3 is phosphorylated by TBK1 and IKKε, ultimately resulting in IFN-β production. When these signaling circuits are dysregulated—particularly through aberrant NF-κB activation—they may impair normal immune responses or amplify chronic inflammation, processes that can foster malignant transformation and tumor progression [ 118 ]. TLRs play critical roles in antiviral defense, prevention of pathogen invasion, and cancer surveillance, functions that are pivotal for coordinating innate and adaptive immune responses, including Th1- and cytotoxic cell–mediated pathways. Beyond these classical roles, TLRs are also capable of recognizing endogenous, host-derived ligands, contributing to tissue repair and the maintenance of physiological homeostasis. Individual TLRs exhibit specialized functions: TLR2 and TLR1 detect various viral protein components, whereas TLR7, TLR8, and TLR9—characterized by high sequence homology—bind a broad spectrum of viral DNA and RNA molecules. The role of TLRs in detecting viral components and activating pro-inflammatory signaling cascades is summarized in Fig. 2 . Fig. 2 TLR-mediated pathogen recognition and inflammatory signaling in HPV-associated ovarian carcinogenesis. This figure shows TLR signaling triggered by viral and bacterial PAMPs. Activation of MYD88- and TRIF-dependent pathways induces NF-κB and IRF3 signaling, promoting type I interferon and cytokine release, thereby linking HPV recognition to inflammation and ovarian tumorigenesis TLR-mediated pathogen recognition and inflammatory signaling in HPV-associated ovarian carcinogenesis. This figure shows TLR signaling triggered by viral and bacterial PAMPs. Activation of MYD88- and TRIF-dependent pathways induces NF-κB and IRF3 signaling, promoting type I interferon and cytokine release, thereby linking HPV recognition to inflammation and ovarian tumorigenesis Functionally, TLR activation enhances NK cell cytotoxicity, induces targeted apoptosis, promotes DC maturation, and facilitates antigen uptake, processing, and presentation by APCs. Furthermore, TLRs upregulate the expression of inflammatory cytokines such as IL-6 and IL-12, interferons including IFN-I and IFN-γ, C-C chemokine receptor 7 (CCR7), and MHC molecules. Notably, cancer cells can exploit TLR expression to modulate the immune microenvironment in a manner that supports tumor progression and malignancy [ 196 ]. During HPV infection, TLR4 and TLR9 expression varies [ 196 ]. Myeloid differentiation primary response protein (MyD88), TIR domain-containing adapter molecule 1 (TRIF), interleukin-1 receptor-associated kinase-like (IRAK) 2, TNF receptor-associated factor (TRAF) 6, I-κB kinase beta (IKKβ), and I-κB kinase epsilon (IKKε) are the six TLR pathway proteins that have been demonstrated to interact with HPV16 E6. The area that contains the catalytic site of the enzyme is also where IKKε and E6 interact, indicating that E6 has an impact on the activation of the IKKε target protein. This interaction raises the possibility that HPV16 E6 significantly influences the host immune response. E6 may improve viral persistence and contribute to the oncogenic processes linked to HPV infection by affecting the IKKε pathway. Lucas et al. demonstrated that HPV16 E6 potentiates NF-κB activation through multiple components of the TLR signaling pathway. Their findings indicate that HPV16 can modulate elements of the host immune response, thereby contributing to its oncogenic potential and playing a significant role in HPV-associated carcinogenesis [ 197 ]. HPV undermines host immune defenses by altering toll-like receptor (TLR) expression and disrupting associated signaling cascades. One of its key effects is the suppression of IL-12, which diminishes the production of type I interferons (IFNs) and IFN-γ. This reduction compromises the activity of macrophages (M1 phenotype) and DCs. In parallel, HPV downregulates HLA expression and impairs its trafficking to the cell surface, thereby blocking antigen presentation, T-cell activation, and the cytotoxic functions of NK and CTL cells. Collectively, these immune evasion strategies weaken lymphocyte function and impair adaptive immune activation through reduced APC (M1 and DC activity [ 198 ]. In the broader context of viral infections, type I IFNs and CTLs represent central components of antiviral immunity. Type I IFNs initiate a signaling cascade that activates the interferon-stimulated gene factor 3 (ISGF3) complex—comprising STAT1, STAT2, and IRF3. Once phosphorylated, ISGF3 translocates into the nucleus and drives the transcription of antiviral genes, including protein kinase R (PKR) and 2′-5′ oligoadenylate synthetase (OAS). PKR restricts the proliferation of virus-infected cells, whereas OAS limits viral replication by promoting nucleotide degradation [ 199 ]. Soluble mediators secreted by neoplastic cells—most notably IL-6 and macrophage colony-stimulating factor-1 (CSF-1)—play a pivotal role in shaping the tumor microenvironment by influencing the differentiation and functional programming of myeloid-derived cells. These factors promote the polarization of immature myeloid cells toward a macrophage-like phenotype, giving rise to a specialized population known as TAMs [ 200 , 201 ]. TAMs constitute a major cellular component of the inflammatory infiltrates within tumor tissues and are actively recruited through chemotactic signals such as monocyte chemoattractant protein-1 (MCP-1) and other cytokines and chemokines. Once localized within the tumor microenvironment, TAMs predominantly acquire an M2-like immunosuppressive phenotype, which is closely associated with tissue remodeling, angiogenesis, and suppression of anti-tumor immunity. These M2-polarized TAMs serve as critical modulators of the dynamic interplay between chronic inflammation and tumor progression [ 202 , 203 ]. Interestingly, TAMs exhibit a dual and context-dependent role in cancer biology. Under specific stimulatory conditions—such as exposure to interleukin-2 (IL-2), interferon-gamma (IFN-γ), and IL-12—TAMs can be reprogrammed toward a pro-inflammatory M1-like phenotype, capable of exerting cytotoxic effects against tumor cells. This reprogramming enhances their antigen-presenting capacity and promotes CTLs activation. However, in most tumor settings, TAMs predominantly secrete IL-10), a potent anti-inflammatory cytokine that suppresses CTL-mediated immune responses and facilitates immune evasion by tumor cells [ 204 ]. This immunosuppressive function of TAMs not only contributes to tumor growth and metastasis but also poses a significant barrier to effective immunotherapy. Therefore, targeting TAMs—either by inhibiting their recruitment (e.g., via CSF1R blockade) or by reprogramming their phenotype—has emerged as a promising strategy in cancer treatment [ 201 ]. The principal PRR families implicated in HPV recognition include TLRs, NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and AIM2-like receptors (ALRs), each characterized by distinct cellular localization, ligand specificity, and downstream signaling pathways [ 205 ]. TLRs are transmembrane receptors situated either on the plasma membrane or within endosomal compartments, where they identify extracellular or endosomal PAMPs. In the context of HPV infection, TLR3 and TLR9 are particularly relevant, as they recognize double-stranded RNA and unmethylated CpG motifs in viral DNA, respectively. Ligand engagement triggers signaling cascades via adaptor proteins such as MyD88 and TRIF, culminating in the activation of transcription factors NF-κB and IRF3/7 and the subsequent production of pro-inflammatory cytokines and type I interferons. However, HPV actively suppresses these pathways. The E6 and E7 proteins downregulate TLR9 expression and inhibit NF-κB activity, while the E1 protein interferes with TRIF-dependent signaling, thereby attenuating IRF3 phosphorylation and reducing IFN-β synthesis [ 118 , 191 ]. NLRs are cytoplasmic sensors that detect intracellular PAMPs and DAMPs. Members such as NOD1 and NOD2 recognize bacterial peptidoglycan fragments and activate RIP2 kinase, leading to NF-κB and MAPK pathway activation. NLRP3, another key NLR, assembles inflammasome complexes with ASC and caspase-1, facilitating the maturation of IL-1β and IL-18 and inducing pyroptotic cell death. In HPV-infected cells, these pathways are frequently suppressed. The E6 and E7 oncoproteins downregulate NOD1 expression, impairing apoptotic signaling and dampening immune activation. Moreover, HPV inhibits NLRP3 inflammasome formation, thereby reducing inflammatory cytokine production and promoting immune evasion [ 206 – 208 ]. RLRs, including RIG-I and MDA5, are cytosolic sensors that detect viral RNA and initiate antiviral signaling through the mitochondrial adaptor MAVS. This interaction activates IRF3 and NF-κB, leading to the transcription of type I interferons and other antiviral genes. Although HPV is a DNA virus, its replication intermediates and host responses may indirectly engage RLR pathways. HPV counteracts these defenses by targeting key regulatory molecules. The E6 protein inhibits TRIM25 and USP15, which are essential for RIG-I activation via ubiquitination. Additionally, the E1 protein suppresses MAVS-mediated signaling, thereby reducing IFN-β production and impairing the expression of interferon-stimulated genes [ 209 , 210 ]. ALRs, such as AIM2 and IFI16, are DNA sensors that detect cytosolic or nuclear double-stranded DNA and initiate inflammasome formation. Upon activation, these receptors recruit ASC and caspase-1, leading to the cleavage of pro-IL-1β and pro-IL-18 into their active forms and triggering pyroptosis. IFI16 is particularly important in HPV-infected keratinocytes, where it senses viral DNA within the nucleus. However, HPV E7 promotes TRIM21-mediated degradation of IFI16, thereby preventing inflammasome assembly and pyroptotic cell death. AIM2 activation may also be modulated by host factors such as TRIM11 and IFI16-β, which compete for DNA binding and regulate inflammasome dynamics [ 211 , 212 ]. Recent findings have revealed that HPV16 E6 oncoprotein suppresses IL-1β secretion not by interfering with transcription or inflammasome activation, but through a post-translational mechanism involving proteasomal degradation of pro-IL-1β via E6-AP and p53 [ 213 ]. Stroe et al. demonstrated that the expression of canonical inflammasome genes, including NLRP3, IL1B, and IL18, is differentially regulated in HPV-infected cervical cells depending on the viral oncogenic potential and lesion severity. Notably, high-grade lesions were associated with reduced IL1B and IL18 transcription, suggesting a potential immune evasion mechanism employed by HPV to promote persistence [ 214 ]. Multimolecular complexes known as inflammasomes activate the cysteine protease caspase-1 in response to endogenous DAMPs like uric acid and extracellular ATP as well as microbial insults to the host, causing inflammation and inflammatory cell death (also known as pyroptosis) [ 215 ]. By inducing antigen presentation and maturation by APCs, including dendritic cells, and secreting pro-inflammatory cytokines, these multiprotein complexes play a critical role in regulating tumor immunity [ 52 ]. An NLR that interacts directly with caspase-1 via a caspase activation and recruitment domain (CARD) or through an adapter protein that connects the NLR to caspase-1—typically apoptosis-associated speck-like protein featuring a caspase recruitment domain (ASC; also called Pycard)—makes up inflammasome complexes [ 216 ]. The DNA sensors DAI and AIM2 and the RNA-sensing RIGlike helicases (RLHs) RIG-I and MDA5 are examples of intracellular nucleic-acid sensing PRRs that work together to offer cytosolic surveillance [ 217 ]. By interacting with the initiator caspase-1, the CARD triggers downstream signaling pathways that activate the executioners. As a proapoptotic mediator, PYD is a member of the death fold domain superfamily, which operates through homotypic interactions. The unique motif BIR makes it easier to recruit adaptor proteins and downstream effectors, whereas the carboxyl-terminus motif LRR has the ability to detect intracellular PAMPs and DAMPs, just like TLRs [ 215 ]. The innate immune response depends heavily on the cGAS-STING signaling pathway, especially when it comes to identifying and reacting to cytosolic DNA, such as that produced by infections or cellular damage. When cytosolic DNA is detected, cyclic GMP-AMP synthase (cGAS) catalyzes the production of cyclic GMP-AMP (cGAMP), which subsequently attaches to and activates the protein known as the Stimulator of Interferon Genes (STING). After cGAMP binding, the transmembrane protein STING, which is mostly found in the endoplasmic reticulum, changes shape, dimerizing and activating as a result. Following its translocation from the endoplasmic reticulum to perinuclear vesicles, activated STING enlists and activates TANK-binding kinase 1 (TBK1) [ 218 ]. STING is activated by the autophagy-associated protein Atg9a, which facilitates its migration from the endoplasmic reticulum (ER) to the Golgi apparatus and then to perinuclear microsomal compartments. This translocation stage is necessary for appropriate signaling since subsequent STING-mediated responses are effectively eliminated when the process is interfered with, for example, by brefeldin A therapy or the production of the Shigella effector protein IpaJ. After settling in the Golgi, STING forms higher-order aggregates that facilitate TBK1 activation, which phosphorylates STING. IRF3 can more easily be recruited to the signaling complex thanks to this post-translational alteration. IRF3 is subsequently phosphorylated by TBK1, which permits its nuclear translocation and the initiation of IFNB1 and several other immune-related gene transcription. Proinflammatory cytokines including IL-6 and TNF-α are produced by this transcriptional pathway, which increases innate immune responses. TBK1 also activates the NF-jB pathway by phosphorylation of IKKab [ 219 ]. Phosphorylation of STING by TBK1 triggers further signaling cascades, such as the phosphorylation of IRF3. An antiviral immune response is eventually promoted by phosphorylated IRF3 translocating to the nucleus, where it triggers the production of type I interferons (IFNs) and other interferon-stimulated genes (ISGs) [ 220 ]. The DNA sensing pathway with cGAS–STING is shown in Fig. 3 . Fig. 3 cGAS–STING DNA-sensing pathway: from HPV recognition to ovarian carcinogenesis. This figure illustrates the cGAS–STING pathway activated by cytosolic dsDNA of viral origin, such as HPV. DNA sensing by cGAS induces cGAMP synthesis, leading to STING activation and downstream TBK1–IRF3 and NF-κB signaling. These cascades drive type I interferon and cytokine release, linking viral recognition to inflammation, immune responses, and HPV-associated ovarian tumorigenesis cGAS–STING DNA-sensing pathway: from HPV recognition to ovarian carcinogenesis. This figure illustrates the cGAS–STING pathway activated by cytosolic dsDNA of viral origin, such as HPV. DNA sensing by cGAS induces cGAMP synthesis, leading to STING activation and downstream TBK1–IRF3 and NF-κB signaling. These cascades drive type I interferon and cytokine release, linking viral recognition to inflammation, immune responses, and HPV-associated ovarian tumorigenesis The Absent in Melanoma 2 (AIM2) inflammasome is a cytosolic DNA sensor that plays a critical role in the innate immune response to viral infections, including human papillomavirus (HPV). AIM2 detects double-stranded DNA (dsDNA) in the cytoplasm—a signal often associated with viral invasion or cellular damage—and initiates the assembly of a multiprotein inflammasome complex. This complex includes the adaptor protein ASC and the effector enzyme pro-caspase-1, which upon activation, cleaves pro-inflammatory cytokines pro-IL-1β and pro-IL-18 into their mature forms, and induces pyroptosis, a form of inflammatory cell death [ 221 , 222 ]. AIM2 contains a C-terminal HIN-200 domain that binds to cytosolic dsDNA in a sequence-independent manner, and an N-terminal PYD domain that interacts with ASC. Upon DNA binding, AIM2 undergoes conformational changes that release the PYD domain, allowing it to oligomerize and recruit ASC. ASC then binds to pro-caspase-1 via its CARD domain, forming a functional inflammasome. Activated caspase-1 cleaves pro-IL-1β and pro-IL-18, which are secreted to amplify the immune response. Caspase-1 also cleaves gasdermin D (GSDMD), whose N-terminal fragment forms pores in the plasma membrane, leading to pyroptosis [ 221 ]. Although AIM2 is not constitutively expressed in keratinocytes, its expression is significantly upregulated in HPV16-positive anal intraepithelial neoplasia and in Langerhans cells of normal skin. Experimental studies have shown that transfection of HPV16 DNA into keratinocytes activates the AIM2 inflammasome, resulting in the release of IL-1β and IL-18 [ 223 ]. Interestingly, AIM2 activation also suppresses IFN-β production, suggesting a regulatory crosstalk between inflammasome signaling and interferon pathways. Blocking AIM2 restores IFN-β secretion, while inhibition of IFI16 enhances IL-1β release, indicating a functional interplay between these DNA sensors [ 194 , 223 ]. The activation of AIM2 in HPV-infected cells contributes to the recruitment of immune cells and the initiation of adaptive immunity. IL-1β promotes local inflammation and T cell activation, while IL-18 induces IFN-γ production in macrophages and NK cells. However, HPV may exploit AIM2 signaling to suppress antiviral interferon responses, thereby facilitating immune evasion and viral persistence. AIM2 activation has also been related to tumor suppression through pyroptosis and tumor-associated macrophage modulation [ 222 ]. Furthermore, studies have shown that the ISG IFI16 ultimately limits HPV replication by causing epigenetic changes in the viral genome. Furthermore, during viral capsid disassembly in the endosome, it has been demonstrated that TLR9 may identify and be activated by the CpG motifs found in the HPV16 E6 gene sequence [ 224 ]. The role of inflammasomes in acute inflammation caused by HPV is shown in Table 2 . Table 2 Role of inflammasomes and DNA sensors in acute inflammation caused by HPV Inflammasome Mechanism in HPV Infection Role in Acute Inflammation/Immunity References AIM2 Binds cytosolic dsDNA (HPV16); oligomerizes with ASC/caspase-1 for IL-1β/IL-18 maturation and GSDMD pores. Induces pyroptosis, IL-1β/IL-18 release for immune cell recruitment (T cells/NK IFN-γ); suppresses IFN-β for evasion. [ 221 – 223 ] IFI16 Detects HPV DNA; epigenetically silences viral promoters; crosstalk with AIM2. Limits replication; boosts IL-1β but restores IFN-β when inhibited. [ 223 , 224 ] cGAS-STING Senses dsDNA; activates IRF3/IFN-β; HPV E7 degrades STING. Amplifies antiviral IFN responses; evasion sustains persistence. [ 194 , 223 ] TLR9 Recognizes CpG motifs in HPV16 E6 during endosomal disassembly. Triggers innate signaling for local inflammation. [ 224 ] Role of inflammasomes and DNA sensors in acute inflammation caused by HPV Induces pyroptosis, IL-1β/IL-18 release for immune cell recruitment (T cells/NK IFN-γ); suppresses IFN-β for evasion.

Proinflammatory cytokines and chemokines play a crucial role in the development and progression of OC, significantly influencing the TME dynamics and immune evasion mechanisms [ 110 , 125 ]. In patients with HPV infections, the plasma levels of pro-inflammatory cytokines such as IL-6, IL-8, TNFα, macrophage inflammatory protein 1 alpha (MIP-1α), granulocyte-macrophage colony-stimulating factor (GMCSF), IL-1α, and IL-1β are markedly elevated, followed by a decreased lymphoproliferative response [ 13 ]. These mediators contribute to chronic inflammation within the TME, promoting tumor cell survival, proliferation, and metastasis [ 126 , 127 ]. Chronic inflammation is a sustained and prolonged immune response that can persist for months or years, often leading to significant tissue remodeling and pathological conditions. Unlike acute inflammation, which serves to eliminate pathogens and initiate healing, chronic inflammation fails to resolve and consequently creates a microenvironment conducive to disease progression, including cancer development [ 128 ]. Over the past decades, research has increasingly implicated chronic inflammation as a key driver of tumor initiation, promotion, and progression [ 129 ]. IL-6 is one of the most extensively studied proinflammatory cytokines in OC, strongly associated with poor prognosis in patients with high-grade serous ovarian cancer (HGSOC) [ 130 ]. IL-6 activates the signal transducer and activator of transcription 3 (STAT3) pathway, promoting tumor cell survival, proliferation, and immune suppression. This signaling pathway enhances cancer cell resistance to chemotherapy by upregulating anti-apoptotic genes such as Bcl-2 and Bcl-xL [ 131 , 132 ]. Furthermore, IL-6 stimulates angiogenesis through the upregulation of VEGF, further supporting tumor growth and metastasis [ 133 ]. In addition to IL-6, TNF-α plays a critical role in ovarian carcinogenesis. Like IL-6, TNF-α activates the NF-κB pathway, contributing to cell survival, proliferation, and resistance to apoptosis [ 134 – 136 ]. Elevated levels of TNF-α in the TME induce the secretion of chemokines such as IL-8 and CCL2, which attract immune cells and facilitate tumor progression by enhancing vascular permeability and promoting metastatic dissemination [ 137 , 138 ]. Furthermore, cytokines such as IL-1β and IL-10 are pivotal in shaping the inflammatory microenvironment of OC. IL-1β, produced in response to inflammatory stimuli, promotes tumor growth and metastasis by enhancing tumor angiogenesis and modulating cell adhesion. The activation of the MAPK signaling pathway by IL-1β leads to the secretion of angiogenic molecules, contributing to tumor cell migration and metastasis. On the other hand, IL-10, an immunosuppressive cytokine, creates a permissive environment for tumor progression by inhibiting anti-tumor immune responses. Elevated levels of IL-10 in OC are associated with the recruitment of MDSCs, which further suppress the immune response and aid in immune evasion [ 139 , 140 ]. Chemokines such as CCL2 (MCP-1) and IL-8 play crucial roles in OC progression. CCL2, which is highly expressed in both OC cells and the TME, promotes tumor cell migration, invasion, and angiogenesis by interacting with its receptor CCR2. This interaction activates the MEK/ERK pathway, enhancing OC cell proliferation and invasion. Blocking the CCL2-CCR2 axis has been shown to reduce OC metastasis, highlighting its importance in disease progression. IL-8 also contributes to tumor angiogenesis and metastasis by recruiting neutrophils and increasing the vascular permeability of the TME. High IL-8 levels correlate with poor prognosis and chemotherapy resistance [ 141 , 142 ]. The chemokine CXCL12 (SDF-1), another key player in OC, interacts with its receptor CXCR4 to regulate immune cell migration and promote tumor cell proliferation. The CXCL12/CXCR4 axis is essential for metastasis to the peritoneal cavity, a common site of OC metastasis. Targeting this axis has emerged as a potential therapeutic strategy to prevent metastasis and inhibit tumor progression [ 143 , 144 ]. Additionally, chemokines such as CCL4 and CCL5 have been shown to modulate anti-tumor immune responses. While CCL5 enhances NK cell activation and promotes anti-tumor immunity, CCL4 can inhibit tumor growth by stimulating tumor-specific CD8 + T cell responses. Targeting the inflammatory signaling pathways and chemokine-receptor interactions within the TME holds significant therapeutic potential [ 145 ]. Inhibiting the activity of key cytokines such as IL-6, TNF-α, and IL-8, or blocking the chemokine-receptor interactions, may provide new avenues for treating OC and overcoming the challenges of chemotherapy resistance [ 146 – 148 ]. Chronic inflammation is a sustained and prolonged immune response that can persist for months or years, often leading to significant tissue remodeling and pathological conditions. Unlike acute inflammation, which serves to eliminate pathogens and initiate healing, chronic inflammation fails to resolve and consequently creates a microenvironment conducive to disease progression, including cancer development [ 128 ]. Over the past decades, research has increasingly implicated chronic inflammation as a key driver of tumor initiation, promotion, and progression [ 129 ]. A critical element in this process is the remodeling of the TME, the dynamic milieu surrounding cancer cells, which includes immune cells, stromal fibroblasts, extracellular matrix (ECM), blood vessels, and signaling molecules [ 126 ]. Chronic inflammation may arise from persistent infections, autoimmune diseases, prolonged exposure to irritants, or unresolved acute inflammation. The continuous production of pro-inflammatory cytokines and reactive oxygen and nitrogen species (ROS/RNS) leads to DNA damage, genomic instability, and epigenetic alterations that predispose cells to malignant transformation [ 127 ]. The persistent activation of inflammatory signaling pathways, most notably nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3), creates an environment that supports tumor cell survival and proliferation [ 149 ]. Central to inflammation-driven tumorigenesis are cytokines such as IL-6, TNF-α, and interleukin-1 beta (IL-1β). These molecules activate signaling cascades that not only promote cell proliferation and inhibit apoptosis but also recruit and modulate various immune cells within the TME [ 150 ]. For instance, IL-6 activates STAT3 signaling, which enhances the expression of genes involved in cell cycle progression and angiogenesis. TNF-α and IL-1β further amplify inflammatory responses and induce the production of MMPs, which degrade ECM components [ 151 ]. The TME is composed of cancer cells and a heterogeneous population of stromal and immune cells. Among these, TAMs, MDSCs, regulatory Tregs, and cancer-associated fibroblasts (CAFs) are critical mediators of inflammation-driven remodeling [ 152 ]. TAMs predominantly exhibit an M2-like phenotype in tumors, secreting anti-inflammatory cytokines and growth factors that promote tumor growth, suppress cytotoxic immune responses, and facilitate angiogenesis [ 136 ]. MDSCs contribute to immunosuppression by inhibiting T cell activation and promoting regulatory T cellexpansion [ 153 ]. CAFs remodel the ECM through secretion of MMPs and other proteases, creating pathways for tumor invasion and metastasis [ 154 ]. Chronic inflammation leads to the overexpression of MMPs, which degrade ECM proteins such as collagen and fibronectin. This degradation not only permits tumor cell invasion but also releases ECM-bound growth factors, further stimulating tumor progression [ 155 ]. In addition, cytokines like TGF-β drive fibroblast activation into CAFs, which produce ECM components that stiffen the tissue matrix, influencing cancer cell behavior and mechanotransduction pathways [ 156 ]. Inflammation-induced secretion of VEGF promotes the formation of new blood vessels within tumors. These vessels, often irregular and leaky, create hypoxic regions that further exacerbate inflammation and select for more aggressive cancer phenotypes [ 157 ]. Collectively, these proinflammatory cytokines and chemokines create a complex and dynamic inflammatory microenvironment that supports OC progression by promoting tumor cell survival, angiogenesis, immune evasion, and metastasis [ 158 , 159 ]. Targeting the inflammatory signaling pathways and chemokine-receptor interactions within the TME holds significant therapeutic potential [ 145 ]. Inhibiting the activity of key cytokines such as IL-6, TNF-α, and IL-8, or blocking the chemokine-receptor interactions, may provide new avenues for treating OC and overcoming the challenges of chemotherapy resistance [ 146 – 148 ].Understanding the functions of specific cytokines and chemokines is essential for identifying potential therapeutic targets in OC [ 160 , 161 ].