Physical activity as a molecular modulator to enhance immunotherapy and drug sensitivity in the endometrial cancer-comorbidity continuum.

Effective treatment of endometrial cancer (EC) is frequently challenged by therapeutic resistance, immunosuppressive tumor microenvironments (TME), and patient comorbidities such as hypertension, kidney dysfunction, and metabolic syndrome. While molecular targeted therapies and immunotherapies (e.g., PD-1 blockade) have emerged as transformative approaches, variable drug sensitivity-often exacerbated by the systemic inflammatory and uremic burden of comorbidities-remains a significant hurdle. Building on the integration of molecular oncology and clinical translation, this review examines physical activity not merely as a preventive measure, but as a systems-level molecular modulator capable of enhancing drug sensitivity and immunotherapy efficacy. We synthesize evidence distinguishing preclinical findings from clinical reality, demonstrating that exercise remodels the TME by repolarizing Tumor-Associated Macrophages (TAMs), reducing Myeloid-Derived Suppressor Cells (MDSCs), and enhancing cytotoxic T cell infiltration. Furthermore, we discuss how exercise-induced shear stress promotes eNOS phosphorylation to normalize tumor vasculature and improve renal perfusion, thereby enhancing drug delivery and mitigating nephrotoxicity. We propose an integrated "EC-Comorbidity Continuum" perspective where personalized exercise prescriptions-distinguishing between acute perfusion benefits and chronic immune priming-serve as a non-pharmacological adjuvant to optimize molecular responses and overcome multidrug resistance.