The role of extracellular vesicles in the communication between endometrial cancer cells and tumour-associated macrophages: a review.

Exosomes are vesicles ranging from 30 to 120 nm in size that can be released by all types of living cells. They are formed by the fusion of intracellular multivesicular bodies with the cell plasma membrane and are released into the extracellular environment. Exosomes play crucial roles in intercellular communication and tissue crosstalk (Dilsiz 2024 ; van Niel et al. 2018 ). Once released from the cell surface, exosomes can fuse with the plasma membrane of recipient cells to transfer their contents into the cytoplasm. Proteins on the surface of exosomes can also bind to cell surface receptors on recipient cells, triggering intracellular signal transduction (Kalluri 2016 ). Exosomes carry a variety of cargo molecules, such as metabolites, DNA fragments, messenger RNA (mRNA), long non-coding RNA (lncRNA), microRNA (miRNA), proteins, and lipids, from their originating cells to target cells (Colombo et al. 2014 ; Simpson et al. 2009 ). As a medium for intercellular communication, especially under pathophysiological conditions, exosomes have garnered extensive attention because they play key roles in cancer metastasis and growth (Kalluri 2016 ). Compared with exosomes, microvesicles are larger, with diameters typically ranging from 100 to 1000 nm. They originate from the plasma membrane and are released into the extracellular space after budding and fission. Like exosomes, microvesicles contain transmembrane proteins, soluble cytoplasmic components, lipids, as well as mRNAs and microRNAs, which are involved in intercellular communication among various cell types, such as cancer cells (Al-Nedawi et al. 2008 ; van Niel et al. 2018 ; Xu et al. 2016 ). Apoptotic bodies, with a diameter of approximately 500 to 2000 nm, form through cell membrane budding during apoptosis. Their primary function is to remove apoptotic cells and prevent inflammatory responses (Atkin-Smith et al. 2015 ; Xu et al. 2019 ); thus, they are not discussed in this paper. Cancer-associated fibroblasts (CAFs) are crucial components of the tumour microenvironment and play important roles in tumour growth, metastasis, angiogenesis, and immunosuppression (Anderson and Simon 2020 ; Chen et al. 2024a , b ; Tokhanbigli et al. 2024 ; Wang et al. 2024a , b , 2024a , b ; Zhang et al. 2024a , b , c , d ). Studies have shown that exosomes secreted by CAFs are vital for the development of endometrial cancer. Maida et al. reported that exosomes derived from the endometrial cancer cell line Ishikawa can be transferred to fibroblasts, altering their microRNA expression profile and indicating that exosomes are a means of communication between endometrial cancer cells and CAFs (Maida et al. 2016 ). Bian et al. reported that CAF-derived exosomal collagen triple helix repeat containing 1 can be transferred to endometrial cancer cells to increase the expression of integrin subunit beta 3, which then activates the phosphorylation of focal adhesion kinase at Tyr-397, promoting the migration of endometrial cancer cells (Bian et al. 2024 ). These findings suggest that exosomes facilitate communication between endometrial cells and CAFs and that CAF-derived exosomes play a role in cancer cell migration. Similarly, exosomal nuclear paraspeckle assembly transcript 1 (NEAT1) secreted by CAFs promotes the expression of signal transducer and activator of transcription 3 (STAT3) and chitinase 3-like 1 (YKL-40/CHI3L1) through miR-26a/b-5p. Experiments also demonstrated that NEAT1 promotes tumour growth in vivo via the miR-26a/b-5p–STAT3–YKL-40 axis, thus promoting the progression of endometrial cancer (Fan et al. 2021a , b ). Therefore, CAF-derived exosomes promote the development of endometrial cancer, serving as a means of intercellular communication. MicroRNAs (miRNAs) regulate the expression of genes involved in various cellular processes and are connected to cancer metastasis. A reduction in certain miRNAs in exosomes is also considered a factor that promotes endometrial cancer. For example, the level of miR-320a in CAF-derived extracellular vesicles is significantly decreased, which enhances the development of endometrial cancer through the hypoxia-inducible factor-1 α/vascular endothelial growth factor-A (HIF1α/VEGFA) signalling pathway. When CAF-derived exosomal miR-320a is directly transferred to endometrial cancer cells, its proliferation is inhibited (Zhang et al. 2020 ). Similarly, the progression of endometrial cancer mediated by CAFs is linked to the loss of miR-148b in CAF-derived exosomes. miR-148b can suppress DNA methyltransferase 1 (DNMT1)-induced epithelial–mesenchymal transition by targeting the gene DNMT1, thereby inhibiting endometrial cancer (Li et al. 2019a , b ). Therefore, miRNAs in exosomes generally suppress endometrial cancer, and their decrease promotes cancer development. Studies have shown that the expression of hsa-miR-17-3p, hsa-miR-99b-3p, hsa-miR-193a-5p, and hsa-miR-320d is upregulated in endometrial cancer according to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses and that these genes are considered potential therapeutic targets for this disease (Yao et al. 2023 ). Shi et al. reported that endometrial cancer cells secrete exosomal miR-133a, which may downregulate the expression of Forkhead Box (L2 FOXL2) in endometrial tissues, making FOXL2 a potential biomarker for endometrial cancer (Shi et al. 2020 ). This highlights the importance of miRNAs in exosomes for identifying therapeutic targets and biomarkers for the endometrium. Galectin-3 binding protein (LGALS3BP) has been shown to bind to E-selectin, enabling circulating extracellular vesicles to interact with endothelial cells in distant organs. The expression of LGALS3BP is increased in the tumour tissues and plasma of cancer patients. Studies indicate that LGALS3BP in circulating extracellular vesicles from patients with endometrial cancer is associated with an increased risk of recurrence (Mariscal et al. 2019 ). Additionally, Song et al. reported that exosomal LGALS3BP promotes the proliferation and migration of endometrial cancer cells by activating the PI3K/AKT/VEGFA signalling pathway both in vitro and in vivo. LGALS3BP expression also increases VEGFA levels and vascular density, thereby promoting angiogenesis in endometrial cancer tissues (Song et al. 2021 ). Exosomes in plasma are also crucial in the pathophysiology of endometrial cancer. Serum exosomal miR-27a-5p levels are elevated in patients with polycystic ovary syndrome and facilitate the migration and invasion of endometrial cancer cells by downregulating the expression of suppressor of mothers against decapentaplegic 4 (Che et al. 2020 ). Moreover, patients with endometrial cancer exhibit significantly lower plasma exosomal miR-26a-5p levels. In particular, patients with lymph node metastasis have even lower exosomal miR-26a-5p levels than patients without metastasis do. The increased density of peritumoral lymphatic endothelial hyaluronic acid receptor-1 in these patients correlated negatively with lesion-level miR-26a-5p, suggesting that the loss of miR-26a-5p may induce lymph node metastasis of endometrial cancer (Wang et al. 2022a , b ). This highlights the role of plasma exosomal miRNAs in endometrial cancer metastasis. Moreover, transfer RNA-derived small RNAs (tsRNAs) are also important in endometrial cancer. dsRNA in serum exosomes (tRF-20-S998LO9D) from endometrial cancer tissues and patients is downregulated. This tsRNA can inhibit the proliferation, migration, and invasion of endometrial cancer cells by upregulating SESN2 expression and can promote apoptosis, indicating its potential as a therapeutic target (Qian et al. 2022 ). Extracellular vesicles in plasma also serve as biomarkers for the diagnosis of endometrial cancer. Sommella et al. used label-free quantitative mass spectrometry proteomics to analyse serum exosomes and identify potential biomarkers for endometrial cancer. They reported that the platelet Factor 4 variant, carbonic anhydrase 1, haemoglobin subunit delta, and apolipoprotein E in serum exosomes may serve as potential biomarkers for this disease (Sommella et al. 2022 ). Similarly, Herrero et al. employed ExoGAG technology to purify extracellular vesicles and discovered that extracellular vesicles specifically expressing annexin A2 were present in plasma samples from patients with endometrial cancer. These findings demonstrate that the use of extracellular vesicles as biomarkers can improve the specificity and accuracy of endometrial cancer diagnosis (Herrero et al. 2019 ). The expression level of small heat shock protein was positively correlated with the expression of cytotoxic immune response markers such as perforin and granzyme B. Moreover, the level of small heat shock protein in the serum exosomes of patients with endometrial cancer was increased, suggesting that this protein can be helpful for early diagnosis (Wyciszkiewicz et al. 2019 ). Song et al. reported that circulating plasma exosomal serpin family A member 5 (SERPINA5) levels were elevated in patients with endometrial cancer, suggesting that circulating exosomal SERPINA5 could be a promising diagnostic biomarker for this disease (Song et al. 2022 ). Additionally, circulating miRNA in serum is a promising biomarker for endometrial cancer. Plasma-derived exosomal miR-15a-5p has emerged as a reliable and effective early detection biomarker, with studies reporting significantly increased expression of miR-151a-5p, miR-143-3p, miR-195-5p, miR-20b-5p, miR-204-5p, miR-423-3p, and miR-484 in the plasma exosomes of patients with endometrial cancer (Fan et al. 2021a , b ; Iavarone et al. 2024 ; Niebora et al. 2024 ; Zhou et al. 2021a , b ). Studies have also shown that serum lncRNA ROR levels are higher in patients with endometrial cancer than in healthy women, indicating that the lncRNA ROR can be used as a biomarker for endometrial cancer (Wang et al. 2023a , b ). An increasing number of studies have shown that miRNAs can be used as potential targets for tumour therapy (Mandal et al. 2024 ; Pan et al. 2024 ) and that human umbilical cord mesenchymal stem cells have broad research value and application prospects. Pan et al. studied the effects of exosomes derived from human umbilical cord mesenchymal stem cells on endometrial cancer and reported that mesoderm-specific transcripts are the target of exosomal miR-503-3p and that miR-503-3p can inhibit the growth of endometrial cancer cells by targeting mesoderm-specific transcripts, thereby exerting an anti-tumour effect (Pan et al. 2022 ). Li et al. reported that miR-302-loaded extracellular vesicles derived from human umbilical cord mesenchymal stem cells can reduce the expression of cyclin D1 and decrease the expression and phosphorylation of AKT in endometrial cancer cells, which inhibits the proliferation and migration of these cells (Li et al. 2019a , b ). These findings suggest that exosomes from umbilical cord mesenchymal stem cells have an inhibitory effect on endometrial cancer. The mechanism may involve inhibition of the AKT pathway, thus reducing the proliferation and migration of cancer cells. Studies have shown that the expression of miR-765 is significantly downregulated in endometrial cancer tissues and is negatively correlated with the expression of proteolipid protein 2 (PLP2). This downregulation is caused by oestrogen, which suppresses miR-765 and promotes endometrial cancer development. Additionally, exosomes from CD45RO-CD8 + T cells release higher levels of miR-765, and these exosomes limit the development of endometrial cancer by regulating the miR-765/PLP2 axis (Zhou et al. 2021a , b ). These findings indicate that exosomal miR-765 has an inhibitory effect on endometrial cancer and has therapeutic potential. Furthermore, compared with that in normal tissues, the expression level of miR-499 is significantly lower in endometrial cancer tissues and cell lines. Moreover, exosomal miR-449 inhibits cell proliferation in endometrial cancer cells and endothelial cells in vitro. Exosomal miR-449 reduced tumour weight, tumour volume, and capillary density in tumour tissues in vivo, suggesting that exosomal miR-499 can effectively inhibit tumour growth and angiogenesis in endometrial cancer (Jing et al. 2020 ). Therefore, exosomal miRNAs have notable research value for the treatment of adenomyosis. Moreover, research has shown that exosomal miRNAs may serve as biomarkers for endometrial cancer. Roman-Canal et al. studied a method for isolating extracellular vesicles from peritoneal lavage in patients with endometrial cancer and reported that the dysregulation of miRNA-383-5p, miRNA-10b-5p, miRNA-34c-3p, miRNA-449b-5p, miRNA-34c-5p, miRNA-200b-3p, miRNA-2110, and miRNA-34b-3p in extracellular vesicles is most specific and suggested that these miRNAs have potential value as biomarkers for endometrial cancer (Roman-Canal et al. 2019 ). Srivastava et al. evaluated the miRNA content of urine-derived exosomes and reported that the expression of miR-200c-3p changed the most. It is believed that the abundance of miR-200c, combined with the symptoms of endometrial cancer, can be used as a preliminary diagnostic marker for endometrial cancer (Srivastava et al. 2018 ). Additionally, studies have shown that the level of miR-106b in the urine of patients with endometrial cancer is significantly decreased (Záveský et al. 2015 ). Therefore, exosomal miRNAs hold certain significance for the development of non-invasive diagnostic methods for endometrial cancer (Table 2 ). Table 2 Extracellular vesicles of different origins EVs source Predominantly transported molecules Mediated biological effects Potential clinical markers Tumour-derived extracellular vesicles ① CTHRC1 CTHRC1 can be transferred to endometrial cancer cells to increase the expression of ITGB3, which then activates the phosphorylation of Fak at Tyr-397, promoting the migration of endometrial cancer cells (Bian et al. 2024 ) hsa-miR-17-3p, hsa-miR-99b-3p, hsa-miR-193a-5p and hsa-miR-320d (Yao et al. 2023 ) miR-133a (Shi et al. 2020 ) ② NEAT1 NEAT1 encourages tumor growth in vivo via the miR-26a/b-5p-STAT3-YKL-40 axis (Fan et al. 2021a , b ) ③ MMiR-320a MiR-320a is significantly decreased, which enhances the development of endometrial cancer through the HIF1α / VEGFA signaling pathway. When CAF-derived exosome miR-320a is directly transferred to endometrial cancer cells, it inhibits their proliferation (Zhang et al. 2020 ). ④ MiR-148b MiR-148b can suppress DNMT1-induced epithelial–mesenchymal transition by targeting the gene DNMT1, thereby inhibiting endometrial cancer (Li et al. 2019a , b ) Extracellular vesicles derived from plasma ① LGALS3BP LGALS3BP promotes the proliferation and migration of endometrial cancer cells by activating the PI3K/AKT/VEGFA signaling pathways both in vitro and in vivo. LGALS3BP expression also enhances VEGFA levels and increases vascular density, thereby promoting angiogenesis in endometrial cancer tissues (Song et al. 2021 ) PF4V1, CA1, HBD, APOE (Sommella et al. 2022 ) ANXA2 (Herrero et al. 2019 ) small heat shock protein (Wyciszkiewicz et al. 2019 ) SERPINA5 (Song et al. 2022 ) miR-151a-5p, miR-143-3p, miR-195-5p, miR-20b-5p, miR-204-5p, miR-423-3p, and miR-484 (Fan et al. 2021a , b ; Iavarone et al. 2024 ; Niebora et al. 2024 ; Zhou et al. 2021a , b ) lncRNA ROR (Wang et al. 2023a , b ) ② MiR-27a-5p MiR-27a-5p facilitates the migration and invasion of endometrial cancer cells by downregulating the SMAD4 (Che et al. 2020 ) ③ MiR-26a-5p The loss of miR-26a-5p may induce lymph node metastasis of endometrial cancer (Wang et al. 2022a , b ) ④ TRF-20-S998LO9D TRF-20-S998LO9D can inhibit the proliferation, migration, and invasion of endometrial cancer cells by upregulating SESN2 and can promote apoptosis (Qian et al. 2022 ) Extracellular vesicles derived from human umbilical cord mesenchymal stem cells ① MiR-503-3p MiR-503-3p can inhibit the growth of endometrial cancer cells by targeting mesoderm-specific transcripts, thereby exerting an anti-tumour effect(Pan et al. 2022 ) ② MiR-302 MiR-302 can reduce the expression of cyclin D1 and decrease the expression and phosphorylation of AKT in endometrial cancer cells, which inhibits the proliferation and migration of these cells (Li et al. 2019a , b ) Extracellular vesicles from other sources ① MiR-765 Estrogen suppresses miR-765 and promotes endometrial cancer development. miR-765 limits the development of endometrial cancer by regulating the miR-765 / PLP2 axis (Zhou et al. 2021a , b ) miRNA-383-5p, miRNA-10b-5p, miRNA-34c-3p, miRNA-449b-5p, miRNA-34c-5p, miRNA-200b-3p, miRNA-2110 and miRNA-34b-3p (Roman-Canal et al. 2019 ) miR-200c (Srivastava et al. 2018 ) miR-106b (Záveský et al. 2015 ) ② MiR-499 MiR-449 inhibits cell proliferation in endometrial cancer cells and endothelial cells in vitro. miR-449 reduced tumour weight, volume, and capillary density in tumour tissues in vivo, suggesting that exosomal miR-499 can effectively inhibit tumour growth and angiogenesis in endometrial cancer (Jing et al. 2020 ) Extracellular vesicles of different origins hsa-miR-17-3p, hsa-miR-99b-3p, hsa-miR-193a-5p and hsa-miR-320d (Yao et al. 2023 ) miR-133a (Shi et al. 2020 ) LGALS3BP promotes the proliferation and migration of endometrial cancer cells by activating the PI3K/AKT/VEGFA signaling pathways both in vitro and in vivo. LGALS3BP expression also enhances VEGFA levels and increases vascular density, thereby promoting angiogenesis in endometrial cancer tissues (Song et al. 2021 ) PF4V1, CA1, HBD, APOE (Sommella et al. 2022 ) ANXA2 (Herrero et al. 2019 ) small heat shock protein (Wyciszkiewicz et al. 2019 ) SERPINA5 (Song et al. 2022 ) miR-151a-5p, miR-143-3p, miR-195-5p, miR-20b-5p, miR-204-5p, miR-423-3p, and miR-484 (Fan et al. 2021a , b ; Iavarone et al. 2024 ; Niebora et al. 2024 ; Zhou et al. 2021a , b ) lncRNA ROR (Wang et al. 2023a , b ) miRNA-383-5p, miRNA-10b-5p, miRNA-34c-3p, miRNA-449b-5p, miRNA-34c-5p, miRNA-200b-3p, miRNA-2110 and miRNA-34b-3p (Roman-Canal et al. 2019 ) miR-200c (Srivastava et al. 2018 ) miR-106b (Záveský et al. 2015 ) Macrophages were first introduced by Eli Mechnikov at the end of the 19th century. They are innate immune effectors that play vital roles in organ development, tissue homeostasis, and repair (Wynn et al. 2013 ). Monocyte-derived macrophages exhibit a high degree of plasticity, allowing them to differentiate into various phenotypes and perform specific functions on the basis of environmental signalling molecules. This process is known as macrophage polarization (Shapouri-Moghaddam et al. 2018 ). Typically, they differentiate into two main phenotypes: classically activated M1 macrophages and alternatively activated M2 macrophages (Mauro et al. 2016 ). M1 macrophages, also called pro-inflammatory macrophages, can be activated by interferon, lipopolysaccharide, and tumour necrosis factor-α, among other factors (Abumaree et al. 2013 ; Barros et al. 2013 ; Chylikova et al. 2018 ; Mills 2015 ). Additionally, they secrete various pro-inflammatory factors, such as interleukin-12 (IL-12), IL-1β, IL-6, IL-23, and tumour necrosis factor-α, to destroy microorganisms, combat tumours, and promote inflammation (Martinez and Gordon, 2014; Mauro et al. 2016 ; Wang et al. 2014 ; Yamaguchi et al. 2017 ). M2 macrophages, also known as anti-inflammatory macrophages, are divided into four subtypes: a, b, c, and d. M2 macrophages are activated by interleukins, interferons, and transforming growth factors. Functionally, they inhibit inflammation, support angiogenesis and fibrosis, and facilitate tumour development (Hao et al. 2012 ; Liao et al. 2011 ; Mosser and Edwards, 2008; Satoh et al. 2010 ). In addition to the two widely studied phenotypes mentioned above, many others, such as M4, CD14 + decidual macrophages in early pregnancy, and M3, have been studied in cardiac research (Chinetti-Gbaguidi et al. 2015 ; Houser et al. 2011 ). Macrophages can differentiate into various phenotypes under certain stimuli, influencing a range of biological processes. In endometrial cancer, TAMs exhibit mainly M2 polarization, which promotes tumour growth, invasion, and metastasis through the secretion of immunosuppressive factors and increased angiogenesis (Huang et al. 2020 ; Iurchenko et al. 2023 ; Peña et al. 2015 ; Wang et al. 2023a , b ). The M2 polarization of TAMs plays a crucial role in endometrial cancer progression. Jin et al. reported that treatment with low-dose tetrabromobisphenol A can promote macrophage polarization towards M2-like phenotypes, leading to the worsening of endometrial cancer. The mechanism involves the downregulation of suppressor of cytokine signalling (SOCS) by tetrabromobisphenol A, which results in the phosphorylation of JAK and STAT6 (Jin et al. 2021 ). Zhu et al. reported that the absence of NLRP3 causes macrophages in tumours to polarize towards M2-like phenotypes, resulting in the growth, invasion, and metastasis of endometrial cancer cells (Zhu et al. 2023 ). The inactivation of LKB1 causes tumour cells to produce chemokine (C–C motif) ligand 2, which recruits pro-tumour macrophages and promotes endometrial cancer progression (Peña et al. 2015 ). Wang et al. reported that cytokines secreted by macrophages can downregulate progesterone receptor expression, making endometrial cancer cells resistant to progesterone therapy and affecting treatment outcomes (Wang et al. 2023a , b ). Additionally, colony-stimulating factor (CSF)-1 secreted by endometrial cancer cells promotes macrophage migration, and CSF-1-stimulated macrophages further promote the proliferation of endometrial cancer cells, indicating that TAMs facilitate tumour cell growth (Hua et al. 2019 ). Several studies have shown that the infiltration of TAMs is linked to the prognosis of endometrial cancer in patients. In one study, Kübler et al. reported that increased TAM infiltration was associated with advanced International Federation of Gynaecology and Obstetrics stage, high tumour grade, increased lymphatic vessel density, lymphatic vascular space infiltration, and lymph node metastasis. It was also an independent prognostic factor for recurrence-free survival in patients with endometrial cancer (Kübler et al. 2014 ). Similarly, using immunohistochemistry, Matsukawa et al. analysed the samples of 75 patients with endometrial cancer and reported that the number of tumour edge CD68-positive macrophages was high, while the number of CD163-positive macrophages was low, which was related to poor prognosis in patients with endometrial cancer (Matsukawa et al. 2024 ). Asaka et al. reported that the number of CD68 + TAMs increased in endometrial cancer patients with high glutaminase expression, which was associated with an immunosuppressive tumour microenvironment and affected prognosis in patients (Asaka et al. 2024 ).

Tumour-derived extracellular vesicles play a crucial role in the progression of endometrial cancer. Additionally, extracellular vesicles from plasma and other sources can either inhibit or promote the development of disease. Researchers have shown that certain miRNAs within extracellular vesicles in serum may serve as potential biomarkers for endometrial cancer. Likewise, miRNAs in extracellular vesicles could be targeted for tumour therapy. Extracellular vesicles play crucial roles in the proliferation, migration, invasion, angiogenesis, and epithelial–mesenchymal transition of endometrial cancer, with many of these processes involving interactions between extracellular vesicles and macrophages. Notably, M2 macrophage polarization is linked to poor prognosis in many cancers, including endometrial cancer and other cancers, and circRNAs in M2 macrophage-derived exosomes contribute to reducing the radiosensitivity of endometrial cancer cells. Exosomes from endometrial cancer cells can promote the polarization of M2-like macrophages, creating a vicious cycle. Therefore, extracellular vesicles in endometrial cancer are highly important as a communication link between macrophages and cancer cells. Blocking the transfer of extracellular vesicles between M2-like macrophages and endometrial cancer cells may be a promising therapeutic strategy. Interrupting this communication prevents M2-like macrophages from promoting the proliferation and migration of cancer cells and inhibits M2 polarization caused by exosomal miRNAs from endometrial cancer cells. Consequently, exploring extracellular vesicles as a transmission pathway between macrophages and endometrial cancer cells is vital. Further studies on the role of macrophages and extracellular vesicles in endometrial cancer are necessary to develop new treatment approaches.

Extracellular vesicles (EVs)—exosomes, microvesicles, and apoptotic bodies—are released by cells and are commonly used for intercellular communication. EVs can alter and influence the function of target cells because they carry various cellular contents, such as lipids, proteins, mRNA, miRNA, and DNA, which can be transferred to target cells to perform their functions (Mulcahy et al. 2014 ; Rana and Zöller 2011 ; Raposo and Stoorvogel 2013 ; Xu et al. 2016 ). EVs play a significant role in the pathophysiology of endometrial cancer. For instance, exosomes are linked to epithelial–mesenchymal transition, endometrial cancer cell proliferation, and angiogenesis in endometrial cancer (Esfandyari et al. 2021 ). Studies have also shown that there is close communication between exosomes involved in the pathology of endometrial cancer and macrophages. For example, exosomal miRNA-21 released by endometrial cancer cells under hypoxic conditions can promote the polarization of M2-like macrophages, which is associated with immune mechanisms involved in the development of endometrial cancer (Xiao et al. 2020 ). Tumour-associated macrophages (TAMs) play a vital role in the immune microenvironment of endometrial cancer. TAMs are derived mainly from monocytes. These monocytes are specifically recruited into the tumour microenvironment and polarize into macrophages with different functions depending on various stimuli, which can either promote or inhibit tumour development (Cassetta et al. 2019 ; Ghebremedhin et al. 2024 ; Ou et al. 2024 ; Xue et al. 2024 ). For instance, when macrophages adopt an immunosuppressive M2-like phenotype, they promote tumour cell growth, invasion, and metastasis (Chen et al. 2024a , b ; Liu et al. 2024 ; Lu et al. 2024 ; Zhang et al. 2024a , b , c , d ). Conversely, M1-like macrophages mediate anti-tumour effects, producing tumour immune-related vascular factors such as IL-12 and CXCL10, along with other pro-inflammatory factors, to combat tumours (An et al. 2024 ; Sun et al. 2023 ; Teng et al. 2024 ; Zhen et al. 2024 ). Extracellular vesicles derived from multiple sources play crucial roles in the initiation and progression of endometrial cancer. Specifically, extracellular vesicles facilitate communication between endometrial cancer cells and immune cells. They play a crucial role in the development of endometrial cancer by interacting with TAMs. Therefore, in this paper, we discuss the role of extracellular vesicles and TAMs in endometrial cancer and aim to clarify the complex interactions between extracellular vesicles and macrophages (Table 1 ). Table 1 Pathohistological classification of endometrial cancer Pathohistological classification of endometrial cancer Characteristics Prognosis Endometrioid Carcinoma Estrogen-related, glandular architecture, well-differentiated Most endometrioid carcinomas have a favourable prognosis and a better prognosis compared to non-estrogen-dependent types. Serous Carcinoma Non-estrogen-dependent, frequent TP53 mutations, papillary structure, highly invasive Account for more than 50% of recurrences and deaths, with a poor prognosis even in the early stage. Clear-cell Carcinoma Non-endometrioid type, invasive, unrelated to estrogen, poor prognosis, and high risk of lymph node metastasis Clear cell carcinoma predicts a poorer survival rate. Carcinosarcoma A special subtype with monoclonal origin, lymphatic and transperitoneal spread, and a 50% recurrence rate Poor prognosis. Reference from Ulrich ( 2011 ) and Amant et al. ( 2005 ). Pathohistological classification of endometrial cancer Reference from Ulrich ( 2011 ) and Amant et al. ( 2005 ).

Macrophages are among the most important cell types in the local microenvironment and can be recruited to remove ectopic fragments. TAMs are the main regulators of endometrial cancer development and polarize into different functional states in response to various stimuli, playing both anti-tumour and tumour-promoting roles in tumour progression (Sun et al. 2023 ; Yang et al. 2020 ). M2-like macrophages promote the proliferation, migration, and invasion of cancer cells and are closely linked to poor clinical outcomes in many malignant tumours (Komohara et al. 2016 ; Liu et al. 2021 ). Additionally, dysfunction in macrophage phagocytosis impacts endometrial cancer. For example, nucleophosmin/B23 induces CD24 expression during endometrial tumorigenesis, helping cancer cells evade macrophage phagocytosis. Active haem metabolism in endometrial cancer cells reduces macrophage phagocytosis by regulating TLR4-mediated IFN Iα secretion and CD36 expression, further promoting immune escape of these cells (Lin et al. 2021 ; Zhang et al. 2024a , b , c , d ). The relationship between extracellular vesicles and macrophages is very close. Extracellular vesicles are highly important for macrophage polarization and immune escape. Moreover, macrophage-derived extracellular vesicles significantly influence endometrial cancer progression (Fig.  1 ). Fig. 1 Extracellular vesicles mediate communication between endometrial cancer cells and tumour-associated macrophages. EVs are secreted from the surface of endometrial cancer cell membranes and contain various contents: proteins (such as TGF-β, interleukins, etc.), non-coding RNAs (like miRNA), and others. EVs migrate to the tumour microenvironment through the bloodstream or by direct contact. Macrophages phagocytose the EVs: M1-type macrophages are inhibited, while M2-type macrophages are activated and play a role in promoting tumour development, specifically through immunosuppression, angiogenesis, promotion of tumor growth, and further stimulation of cancer cells to secrete more EVs, creating a positive feedback loop Extracellular vesicles mediate communication between endometrial cancer cells and tumour-associated macrophages. EVs are secreted from the surface of endometrial cancer cell membranes and contain various contents: proteins (such as TGF-β, interleukins, etc.), non-coding RNAs (like miRNA), and others. EVs migrate to the tumour microenvironment through the bloodstream or by direct contact. Macrophages phagocytose the EVs: M1-type macrophages are inhibited, while M2-type macrophages are activated and play a role in promoting tumour development, specifically through immunosuppression, angiogenesis, promotion of tumor growth, and further stimulation of cancer cells to secrete more EVs, creating a positive feedback loop Low expression of miR-192-5p in tumour-associated macrophage-derived exosomes promoted the expression of interleukin 1 receptor-associated kinase 1 (IRAK1) mRNA and nuclear factor kappa B (NF-κB) mRNA in tumours, whereas overexpression of miR-192-5p inhibited the expression of IRAK1 and NF-κB in tumour tissues and reduced NF-κB phosphorylation. Therefore, IRAK1 may be a downstream target of miR-192-5p, and exosomes overexpressing miR-192-5p promote the apoptosis of endometrial cancer cells by inhibiting the IRAK1/NF-κB signalling pathway (Wang et al. 2022a , b ). Studies have shown that the expression of circular RNA (circRNA) is significantly different in patients with endometrial cancer (Xu et al. 2018 ) and that hsa_circ_0001610 is abundant in M2-polarized macrophage-derived exosomes. Since hsa_circ_0001610 acts as a competitive endogenous RNA of miR-139-5p, it can upregulate the expression of cyclin B1. Cyclin B1 plays an important role in promoting radioresistance in several types of cancers by regulating the cell cycle. Therefore, tumour-associated macrophage-derived exosomal hsa_circ_0001610 is transferred to endometrial cancer cells. The overexpression of hsa_circ_0001610 in endometrial cancer cells promotes cyclin B1 expression through the binding of miR-139-5p, reducing the radiosensitivity of these cells (Gu et al. 2021 ), which may induce tumour recurrence. Macrophage-derived extracellular vesicles can promote the apoptosis of endometrial cancer cells, but the use of these vesicles for treatment still needs more in-depth exploration. Although macrophage-derived extracellular vesicles have potential, studies have shown that the overexpression of circRNAs in M2 macrophage-derived exosomes might decrease the radiosensitivity of endometrial cancer cells. As a result, the specific role of macrophage-derived extracellular vesicles in endometrial cancer remains unclear. All these factors increase the complexity of basic research in this area but also highlight its potential for future studies. TAMs tend to develop a polarized M2 phenotype in various tumour diseases, which is linked to poor tumour prognosis. Studies have shown that exosomes from ectopic endometrial stromal cells can promote M2 polarization, leading to the accumulation of M2-like macrophages in the peritoneal microenvironment of patients and accelerating the growth and blood vessel formation of ectopic lesions (Sun et al. 2022 ). Similarly, research in endometrial cancer has indicated that the presence of M2-like macrophages is negatively associated with disease prognosis. Li et al. found that, under hypoxic conditions, endometrial cancer cells produce higher levels of exosomal miRNA-21, which can be transferred to monocytes. They reported that miRNA-21 mimics promote the polarization of THP-1 cells into M2-like macrophages. Therefore, the pathway involved in the polarization of M2-like macrophages may be key to the development of the immune microenvironment during endometrial cancer progression (Xiao et al. 2020 ). Studies have shown that the expression of the lncRNA TRPM2-AS and secreted phosphoprotein 1 is abnormally increased in endometrial cancer tissues and cells. Ma et al. reported that TRPM2-AS plays an important role in regulating the tumour immune microenvironment of endometrial cancer. Overexpression of TRPM2-AS in endometrial cancer cells leads to significant expression of secreted phosphoprotein 1 in exosomes and stimulates the expression of M2-like macrophage markers such as CD163 and CD206. These findings suggest that endometrial cancer cells induce the polarization of M2-like macrophages by secreting exosomes rich in secreted phosphoprotein 1, thereby promoting the progression of endometrial cancer (Ma et al. 2024 ). Conversely, Zhou et al. reported that the lncRNA NIFK-AS1 inhibits IL-4-induced M2-like macrophage polarization by targeting miR-146a and reducing oestrogen-induced proliferation, migration, and invasion of endometrial cancer cells (Zhou et al. 2018 ). M2 macrophage polarization promotes tumour proliferation and metastasis and is associated with poor prognosis. In endometrial cancer, the infiltration of M2-like macrophages is also negatively correlated with prognosis. Furthermore, exosomes derived from endometrial cancer cells facilitate the polarization of M2-like macrophages, creating a vicious cycle. Disrupting this transmission pathway of extracellular vesicles could offer potential therapeutic value in treating endometrial cancer.