Work

Glucagon-like peptide-1 receptor agonism improves lung cancer outcomes and tumor growth control

Year: 2025

Type: article

Abstract: BACKGROUND: Emerging evidence indicates a reduced incidence of multiple cancers in users of glucagon-like peptide-1 receptor agonists (GLP-1RAs), drugs widely used for glycemic control and weight reduction that modulate several key regulators of metabolism. We sought to examine their association with non-small cell lung cancer (NSCLC) outcomes in overweight and obese patients and gain mechanistic insights from mouse models. METHODS: Two clinical cohorts of overweight and obese patients with NSCLC - one undergoing surgical resection (n = 1,177, 71 GLP-1RA users) and another receiving immune checkpoint inhibitors (n = 300, 10 GLP-1RA users), were propensity score matched for relevant covariates and analyzed for clinical outcomes. RESULTS: GLP-1RA use was associated with increased recurrence-free survival in overweight and obese patients (HR: 0.41, 95% CI: 0.16-1.04, P = 0.026) after lobectomy. GLP-1RA treatment reduced tumor burden in obese but not normal-weight mice and altered the frequency and phenotypes of leukocyte populations and gene expression patterns in obese tumors, crucial to cancer progression and antitumor immunity. Concurrent GLP-1RA and immunotherapy was also associated with improved overall (HR: 0.41, 95% CI: 0.16-1.01, P = 0.027) and progression-free survival (HR: 0.31, 95% CI: 0.10-0.94, P = 0.019) for patients with advanced NSCLC. CONCLUSIONS: In our cohort, GLP-1RAs enhanced lung cancer-specific clinical outcomes and augment immunotherapy efficacy. Preclinical evidence suggested this effect to be obesity restricted and mediated by immune modulation of the tumor microenvironment. FUNDING: George Duke, Department of Defense (W81XWH-21-1-0377), NIH/NIGMS (GM147497), American Cancer Society (RSG-22-071-01-TBE), NIH (1R01 CA255515-01A1), NIH/NCI (P30CA013696 and P30CA016056).

Source: JCI Insight

DOI: 10.1172/jci.insight.195484