Obesity promotes aggressiveness of endometrial cancer via metabolic reprogramming and intercellular crosstalk in the tumor microenvironment.

Endometrial cancer is one of the most prevalent malignancies of the female reproductive system, and the global rising prevalence of obesity has further increased its incidence and poor clinical prognosis. Although obesity is recognized as a critical modifiable risk factor for endometrial cancer, it remains unclear whether and how obesity drives tumor initiation and progression by modulating the tumor microenvironment at single-cell resolution. Using a genetic mouse model with pten conditional knockout in the uterine endometrium, clinical samples from endometrial cancer patients, and single-cell RNA sequencing from 10 endometrial tumor samples, we delineated a comprehensive single-cell atlas of endometroid endometrial cancer altered by obesity. The results reveal a unique SOX9+LGR5+ epithelial subpopulation exhibiting cancer stem cell features, which establishes an intratumoral estrogen-signaling circuit. Tumor-associated macrophages and NK/T cells undergo profound metabolic reprogramming toward pro-tumor and immunosuppressive phenotypes. Fibroblasts exhibit remarkable phenotypic and metabolic rewiring within a lipid-rich microenvironment, facilitating extracellular matrix remodeling. Emerging endothelial subsets drive angiogenesis and vascular dysfunction, fostering intratumoral hypoxia and cancer cell metastasis. These components engage in extensive intercellular crosstalk centered on tumor-associated macrophages, forming a self-reinforcing network that drives immunosuppression, stemness maintenance, cell migration, and aberrant angiogenesis. Our findings highlight that obesity-induced tumor microenvironment remodeling and metabolic communication constitute key mechanisms underlying tumor aggressiveness of obesity-related endometrial cancer, providing novel mechanistic insights and potential therapeutic targets for clinical intervention.