Repositioning GLP-1 Receptor Agonists in Endometrial Cancer: Molecular Rationale, Preclinical Insights, and Translational Opportunities.

Endometrial cancer incidence and mortality are rising globally, largely driven by the obesity epidemic. Treatment options remain limited for obesity-associated, hormone-resistant, or fertility-preserving endometrial cancer, highlighting the need for novel therapies that address both tumor biology and metabolic dysfunction. In this study, we synthesize the molecular rationale, preclinical, population-based, and emerging clinical trial evidence on glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1 RA) in endometrial cancer. GLP-1R is expressed in benign and malignant endometrial tissues, where activation of cAMP-PKA and AMPK-mTOR signaling has been shown to mediate antiproliferative, proapoptotic, and autophagy-inducing effects. Preclinical models demonstrate that class-wide GLP-1 RAs may restore progesterone receptor expression, overcome hormone resistance, and synergize with progestin therapy; however, the effects may vary by agent. Retrospective studies suggest that combining GLP-1 RAs with local progestin therapy, commonly a levonorgestrel-releasing intrauterine device (preferred in obesity because oral progestin bioavailability is reduced), is associated with a reduced risk of endometrial cancer in high-risk women. Ongoing clinical trials are assessing their role in fertility-sparing settings-evaluating complete response to progestin-based therapy, relapse rates, and time to conception outcomes-as well as in adjuvant settings, in which disease-free survival is a key endpoint; however, gastrointestinal tolerability and the absence of long-term safety data in endometrial cancer populations remain important considerations. As a class, GLP-1 RAs represent a promising therapeutic approach to targeting both the obesogenic milieu and tumor-intrinsic pathways in endometrial cancer; however, agent-specific differences warrant attention. Prospective, subtype-stratified trials are essential to establish their role in comprehensive endometrial cancer care.