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).

The prevalence of obesity, defined as the body mass index (BMI) ≥ 30 kg/m², has reached epidemic levels. Obesity is associated with an increased risk of various cancers, including gastrointestinal ones. Recent evidence has suggested that obesity disproportionately impacts males and females with cancer, resulting in varied transcriptional and metabolic dysregulation. This study aimed to elucidate the differences in the metabolic milieu of adenocarcinomas of the gastrointestinal (GI) tract both related and unrelated to sex in obesity. To demonstrate these obesity and sex-related effects, we utilized three primary data sources: serum metabolomics from obese and non-obese patients assessed via the Biocrates MxP Quant 500 mass spectrometry-based kit, the ORIEN tumor RNA-sequencing data for all adenocarcinoma cases to assess the impacts of obesity, and publicly available TCGA transcriptional analysis to assess GI cancers and sex-related differences in GI cancers specifically. We applied and integrated our unique transcriptional metabolic pipeline in combination with our metabolomics data to reveal how obesity and sex can dictate differential metabolism in patients. Differentially expressed genes (DEG) analysis of ORIEN obese adenocarcinoma as compared to normal-weight adenocarcinoma patients resulted in large-scale transcriptional reprogramming (4029 DEGs, adj. p < 0.05 and |logFC| > 0.58). Gene Set Enrichment and metabolic pipeline analysis showed genes enriched for pathways relating to immunity (inflammation, and CD40 signaling, among others) and metabolism. Specifically, we found alterations to steroid metabolism and tryptophan/kynurenine metabolism in obese patients, both of which are highly associated with disease severity and immune cell dysfunction. These findings were further confirmed using the TCGA colorectal adenocarcinoma (CRC) and esophageal adenocarcinoma (ESCA) data, which showed similar patterns of increased tryptophan catabolism for kynurenine production in obese patients. These patients further showed disparate alterations between males and females when comparing obese to non-obese patient populations. Alterations to immune and metabolic pathways were validated in six patients (two obese and four normal weight) via CD8+/CD4+ peripheral blood mononuclear cell RNA-sequencing and paired serum metabolomics, which showed differential kynurenine and lipid metabolism, which corresponded with altered T-cell transcriptome in obese populations. Overall, obesity is associated with differential transcriptional and metabolic programs in various disease sites. Further, these alterations, such as kynurenine and tryptophan metabolism, which impact both metabolism and immune phenotype, vary with sex and obesity together. This study warrants further in-depth investigation into obesity and sex-related alterations in cancers that may better define biomarkers of response to immunotherapy.