Metabolic interplay between endometrial cancer and tumor-associated macrophages: lactate-induced M2 polarization enhances tumor progression
Abstract Tumor-associated macrophages (TAMs), abundant within the tumor microenvironment, are key mediators of immunosuppression and represent promising therapeutic targets. Metabolic crosstalk between tumor cells and TAMs is a critical regulator of immune phenotype switching. However, the interacti...
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BMC
2025-08-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06235-6 |
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| author | Xiaodie Liu Heming Sun Jing Liang Huan Yu Ming Xue Yuebo Li Wenhui Li Ying Xu Bin Ling Dingqing Feng |
| author_facet | Xiaodie Liu Heming Sun Jing Liang Huan Yu Ming Xue Yuebo Li Wenhui Li Ying Xu Bin Ling Dingqing Feng |
| author_sort | Xiaodie Liu |
| collection | DOAJ |
| description | Abstract Tumor-associated macrophages (TAMs), abundant within the tumor microenvironment, are key mediators of immunosuppression and represent promising therapeutic targets. Metabolic crosstalk between tumor cells and TAMs is a critical regulator of immune phenotype switching. However, the interactions between endometrial cancer (EC) cells and TAMs remain incompletely understood. Here, we demonstrate that EC cells exhibit increased aerobic glycolysis, as confirmed by bulk transcriptomics, extracellular lactate measurements, RT-PCR, and immunohistochemistry. M2-polarized TAMs were significantly more prevalent in EC tissues compared to normal endometrium, and this prevalence correlated with deep myometrial invasion and advanced stages. In vitro assays revealed that EC cell-derived lactate promotes M2 polarization of macrophages, enhancing epithelial-mesenchymal transition and angiogenesis, thereby increasing EC cell invasiveness and metastasis. Cytokine profiling and functional assays further demonstrated that lactate-stimulated M2 TAMs secrete elevated IL-6, which promotes tumor progression. Importantly, blocking IL-6 signaling significantly reduced the M2 TAM-mediated effects on EC cells in vitro and inhibited tumor growth and metastasis in vivo. Our study underscores the pivotal role of aerobic glycolysis-derived lactate in inducing TAM M2 polarization and highlights the IL-6 axis as a therapeutic target, offering new strategies for treating EC by disrupting metabolic-immune crosstalk. |
| format | Article |
| id | doaj-art-3f69c6f722ee42e59e33174170d80c39 |
| institution | DOAJ |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-3f69c6f722ee42e59e33174170d80c392025-08-20T03:06:51ZengBMCJournal of Translational Medicine1479-58762025-08-0123111810.1186/s12967-025-06235-6Metabolic interplay between endometrial cancer and tumor-associated macrophages: lactate-induced M2 polarization enhances tumor progressionXiaodie Liu0Heming Sun1Jing Liang2Huan Yu3Ming Xue4Yuebo Li5Wenhui Li6Ying Xu7Bin Ling8Dingqing Feng9Department of Obstetrics and Gynecology, China-Japan Friendship HospitalInstitute of Clinical Medical Sciences, China-Japan Friendship HospitalDepartment of Obstetrics and Gynecology, China-Japan Friendship HospitalDepartment of Obstetrics and Gynecology, China-Japan Friendship HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeChinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Obstetrics and Gynecology, China-Japan Friendship HospitalDepartment of Obstetrics and Gynecology, China-Japan Friendship HospitalDepartment of Obstetrics and Gynecology, China-Japan Friendship HospitalDepartment of Obstetrics and Gynecology, China-Japan Friendship HospitalAbstract Tumor-associated macrophages (TAMs), abundant within the tumor microenvironment, are key mediators of immunosuppression and represent promising therapeutic targets. Metabolic crosstalk between tumor cells and TAMs is a critical regulator of immune phenotype switching. However, the interactions between endometrial cancer (EC) cells and TAMs remain incompletely understood. Here, we demonstrate that EC cells exhibit increased aerobic glycolysis, as confirmed by bulk transcriptomics, extracellular lactate measurements, RT-PCR, and immunohistochemistry. M2-polarized TAMs were significantly more prevalent in EC tissues compared to normal endometrium, and this prevalence correlated with deep myometrial invasion and advanced stages. In vitro assays revealed that EC cell-derived lactate promotes M2 polarization of macrophages, enhancing epithelial-mesenchymal transition and angiogenesis, thereby increasing EC cell invasiveness and metastasis. Cytokine profiling and functional assays further demonstrated that lactate-stimulated M2 TAMs secrete elevated IL-6, which promotes tumor progression. Importantly, blocking IL-6 signaling significantly reduced the M2 TAM-mediated effects on EC cells in vitro and inhibited tumor growth and metastasis in vivo. Our study underscores the pivotal role of aerobic glycolysis-derived lactate in inducing TAM M2 polarization and highlights the IL-6 axis as a therapeutic target, offering new strategies for treating EC by disrupting metabolic-immune crosstalk.https://doi.org/10.1186/s12967-025-06235-6Endometrial cancerTumor-associated macrophagesMetabolism reprogrammingAerobic glycolysisLactateEpithelial-mesenchymal transition |
| spellingShingle | Xiaodie Liu Heming Sun Jing Liang Huan Yu Ming Xue Yuebo Li Wenhui Li Ying Xu Bin Ling Dingqing Feng Metabolic interplay between endometrial cancer and tumor-associated macrophages: lactate-induced M2 polarization enhances tumor progression Journal of Translational Medicine Endometrial cancer Tumor-associated macrophages Metabolism reprogramming Aerobic glycolysis Lactate Epithelial-mesenchymal transition |
| title | Metabolic interplay between endometrial cancer and tumor-associated macrophages: lactate-induced M2 polarization enhances tumor progression |
| title_full | Metabolic interplay between endometrial cancer and tumor-associated macrophages: lactate-induced M2 polarization enhances tumor progression |
| title_fullStr | Metabolic interplay between endometrial cancer and tumor-associated macrophages: lactate-induced M2 polarization enhances tumor progression |
| title_full_unstemmed | Metabolic interplay between endometrial cancer and tumor-associated macrophages: lactate-induced M2 polarization enhances tumor progression |
| title_short | Metabolic interplay between endometrial cancer and tumor-associated macrophages: lactate-induced M2 polarization enhances tumor progression |
| title_sort | metabolic interplay between endometrial cancer and tumor associated macrophages lactate induced m2 polarization enhances tumor progression |
| topic | Endometrial cancer Tumor-associated macrophages Metabolism reprogramming Aerobic glycolysis Lactate Epithelial-mesenchymal transition |
| url | https://doi.org/10.1186/s12967-025-06235-6 |
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