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Results indicate improved lung cancer–specific outcomes and obesity-restricted immune modulation of the tumor microenvironment, including changes in leukocyte phenotypes and gene expression 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note: AGP and BF contributed equally to this work and are co–first authors.  \nConflict of interest: The authors have declared that no conflict of interest exists.  \nCopyright: © 2025, Pachimatla et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.  \nSubmitted: May 9, 2025  \nAccepted: August 20, 2025  \nPublished: August 26, 2025  \nReference information: JCI Insight. 2025;10(19):e195484 .  \n[https://doi.org/10.1172/jci](https://doi.org/10.1172/jci). insight.195484 .  \nGlucagon-like peptide-1 receptor agonism improves lung cancer outcomes and tumor growth control  \nAkhil Goud Pachimatla,1 Bailey Fitzgerald,2 Joyce Ogidigo,3 Meera Bhatia,1 Randall J. Smith Jr.,4 Kalyan Ratnakaram,1 Sukumar Kalvapudi,1 Yeshwanth Vedire,1 Deschana Washington,4  \nRobert Vethanayagam RR,1 Hua-Hsin Hsiao,5 Spencer Rosario,5 Viraj R. Sanghvi,3,6 Joseph Barbi,1,4 and Sai Yendamuri1  \n1Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, New York, USA. 2Department of Medical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. 3Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York, USA. 4Department of Immunology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, New York, USA. 5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. 6Naomi Berrie Diabetes Research Center, Columbia University Irving Medical Center, New York, New York, USA.  \nBACKGROUND. 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.  \nMETHODS. 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.  \nRESULTS. 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.  \nCONCLUSIONS. 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.  \nFUNDING. 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) .  \nIntroduction  \nGlucagon-like peptide-1 receptor agonists (GLP-1RAs), initially introduced as a class of antidiabetic drugs, have entered widespread use after their recent approval for the treatment of obesity and obesity-related conditions (1) . Several retrospective studies further associate GLP-1RA use with altered cancer incidence, yet the underlying mechanisms remain unclear (2, 3) .  \nAlthough the relationship between obesity and lung cancer risk is co","cbCaida62FRagoM3","https://ap.wps.com/l/cbCaida62FRagoM3","pdf",3874283,16,"English","# Introduction\n# Results\n# Methods\n# Conclusions\n# Funding","[{\"question\":\"What question does the study address regarding GLP-1RAs and lung cancer?\",\"answer\":\"The study examines whether GLP-1RAs are associated with non–small cell lung cancer outcomes in overweight and obese patients and explores underlying mechanisms using mouse models.\"},{\"question\":\"How were patient outcomes assessed in the clinical cohorts?\",\"answer\":\"Two propensity score–matched cohorts were analyzed: one undergoing surgical resection and another receiving immune checkpoint inhibitors, focusing on recurrence-free, overall, and progression-free survival.\"},{\"question\":\"What mechanistic effect of GLP-1RAs is supported by the results?\",\"answer\":\"Preclinical evidence suggests the effect is restricted to obesity and is mediated by immune modulation within the tumor microenvironment, including altered leukocyte frequencies, phenotypes, and tumor gene expression patterns.\"}]","Glucagon-like peptide-1 receptor agonism improves lung cancer outcomes and tumor growth control | PDF",1790218543]