Clinical cancer research : an official journal of the American Association for Cancer ResearchDec 2, 2025

Potential use of GLP-1 receptor activators in treating uterine lining cancer: molecular reasons, lab study results, and future possibilities

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 20, 2026

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may provide a promising therapeutic approach for endometrial cancer treatment.

Endometrial cancer incidence and mortality are rising globally, largely due to the obesity epidemic.
GLP-1 receptors are found in both benign and malignant endometrial tissues, where they may influence cell growth and death.
Preclinical studies indicate that GLP-1 RAs could restore hormone receptor expression and work alongside progestin therapy.
Retrospective studies show a potential association between GLP-1 RAs combined with local progestin therapy and reduced endometrial cancer incidence in high-risk women.
Ongoing clinical trials are investigating the effectiveness of GLP-1 RAs in fertility-sparing treatments and their impact on disease-free survival.
Important considerations include gastrointestinal tolerability and the lack of long-term safety data in endometrial cancer populations.

Simplified

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.

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Potential use of GLP-1 receptor activators in treating uterine lining cancer: molecular reasons, lab study results, and future possibilities

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