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

Endometrial cancer (EC) incidence and mortality is rising globally, largely driven by the obesity epidemic. Treatment options remain limited for obesity-associated, hormone-resistant, or fertility-preserving EC, highlighting the need for novel therapies that address both tumor biology and metabolic dysfunction. Here, we synthesize the molecular rationale, preclinical, population-based, and emerging clinical trial evidence on glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1 RAs) in EC. 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 reduced EC 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—as well as in adjuvant settings, where disease-free survival is a key endpoint; however, gastrointestinal tolerability and the absence of long-term safety data in EC 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 EC; however, agent-specific differences warrant attention. Prospective, subtype-stratified trials are essential to establish their role in comprehensive EC care.