Obesity-specific improvement of lung cancer outcomes and immunotherapy efficacy with metformin

Abstract Background Preclinical cancer studies ascribe promising anticancer properties to metformin. Yet, clinical findings vary, casting uncertainty on its therapeutic value for non–small cell lung cancer (NSCLC) patients. We hypothesized that metformin could benefit obese and overweight patients with NSCLC. Methods We retrospectively analyzed 2 clinical cohorts and employed complementary mouse models to test our hypothesis. One cohort included NSCLC patients with overweight body mass index (≥25 kg/m2, n = 511) and nonoverweight body mass index (<25 kg/m2, n = 232) who underwent lobectomy, evaluating metformin’s impact on clinical outcomes. Another cohort examined metformin’s effect on progression-free survival after immune checkpoint inhibitors in overweight (n = 284) vs nonoverweight (n = 184) NSCLC patients. Metformin’s effects on tumor progression, antitumor immunity, and immune checkpoint inhibitor response in obese and normal-weight mice were assessed with lung cancer models. Results Metformin is associated with increased recurrence-free survival in overweight patients (hazard ratio [HR] = 0.47, 95% confidence interval [CI] = 0.24 to 0.94; P = .035) after lobectomy. It also corrected accelerated tumor growth in diet-induced obese mouse models in a lymphocyte-specific manner while reversing several mechanisms of immune suppression potentiated by obesity. Programmed cell death 1 blockade coupled with metformin was more effective at limiting tumor burden in obese mice and correlated with progression-free survival only in overweight patients on immunotherapy (HR = 0.60, 95% CI = 0.39 to 0.93; P = .024). Conclusions Metformin may improve lung cancer–specific clinical outcomes in obese and overweight lung cancer patients and enhance immunotherapy efficacy in this growing population. This work identifies obesity as a potential predictive biomarker of metformin’s anticancer and immunotherapy-enhancing properties in lung cancer while shedding light on the underlying immunological phenomena.