Objective:

To examine the role of physical activity as a systems-level molecular modulator that enhances drug sensitivity and immunotherapy efficacy in endometrial cancer patients with comorbid conditions.

Approach:

• Impact on Comorbidities: The review discusses how exercise-induced shear stress promotes eNOS phosphorylation, normalizes tumor vasculature, and improves renal perfusion, thereby enhancing drug delivery and mitigating nephrotoxicity.

Key Findings:

• Physical activity is associated with reduced risk of endometrial cancer and improved management of hypertension and kidney dysfunction, as well as influencing biological mechanisms such as body fat reduction, insulin sensitivity, and estrogen regulation, which are critical in cancer development.
• Regular physical activity improves renal hemodynamics and slows declines in glomerular filtration rate.

Interpretation:

The review proposes an integrated 'EC-Comorbidity Continuum' perspective, suggesting personalized exercise prescriptions as a non-pharmacological adjuvant to optimize molecular responses and overcome multidrug resistance.

Limitations:

• The review distinguishes between preclinical findings and clinical reality, indicating that some mechanisms remain hypothetical and may not fully translate to endometrial cancer.

Conclusion:

Physical activity may serve as a targeted molecular intervention to dismantle comorbidity-driven therapeutic barriers in endometrial cancer treatment.