Metabolic interplay between endometrial cancer and tumor-associated macrophages: lactate-induced M2 polarization enhances tumor progression

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.