Endometrial cancer (EC) is a gynecologic malignancy closely associated with disruptions in metabolic processes. A majority of EC patients respond poorly to immunotherapy, highlighting the urgent need to identify novel therapeutic targets at the interface of metabolism and immune regulation. In vitro, a combination of proteomics, CUT&Tag (cleavage under targets and tagmentation) sequencing, dual-luciferase reporter assays, lipidomic profiling, and macrophage–tumor co-culture systems was employed to reveal the dual metabolic and immunomodulatory role of estrogen-related receptor α (ERRα) in KLE and HEC-1A human EC cell lines. Patient-derived organoids were utilized to confirm the therapeutic potential of ERRα inhibition. In vivo, KLE xenografts were used to examine tumor progression and assess treatment efficacy in mice. Clinically, a retrospective cohort of 166 EC patients was analyzed via immunohistochemistry (IHC) to evaluate ERRα expression and macrophage infiltration, allowing correlation with disease features and therapeutic relevance. Multiplex IHC was applied to examine the spatial distribution of M2 macrophages during EC progression.
ERRα directly binds to the PTPMT1 promoter region (-624 to −609 bp), driving its transcription in EC cells. This upregulation enhances cardiolipin biosynthesis, which stabilizes the inner mitochondrial membrane, boosts oxidative phosphorylation (OXPHOS), and increases reactive oxygen species (ROS) levels. Elevated ROS subsequently activates NF-κB signaling, promoting CCL2 secretion and recruiting M2 macrophages into the tumor microenvironment. Combined inhibition of ERRα (XCT790) and CCL2 (carlumab) produced significantly enhanced antitumor effects in EC. Moreover, ERRα expression in patient tissues may serve as a biomarker for disease assessment. These findings uncover a critical role for the ERRα-driven metabolic axis in shaping the immune landscape of EC, linking mitochondrial lipid metabolism to macrophage-mediated immunosuppression. This work provides mechanistic insight supporting combined metabolic–immune-targeted therapies as a strategy to overcome immunotherapy resistance in EC.
