Impact of Angiotensin-Converting Enzyme Inhibitors (ACEIs) on the Efficacy of Immunotherapy in Metastatic NSCLC

Background: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in metastatic non-small cell lung cancer (NSCLC), yet only a subset of patients derives durable benefit, suggesting that host and tumor-related factors may modify treatment efficacy. The renin–angiotensin system has been implicated in regulation of the tumor microenvironment, and angiotensin-converting enzyme inhibitors (ACEIs) have therefore been proposed as potential modulators of immunotherapy response. Material and methods: We conducted a retrospective observational cohort study including patients with advanced metastatic NSCLC treated in the first-line setting with treatment-based immunotherapy, with or without chemotherapy, between January 2017 and September 2025. Chronic ACEI exposure was defined as continuous use for at least two years prior to initiation of immunotherapy. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier estimates and compared using the log-rank test, and multivariable Cox proportional hazards models were adjusted. Results: Among 446 eligible patients, 71 (16%) received ACEIs and 375 (84%) did not. The median age of the cohort was 67.5 years, and 70% were male. Adenocarcinoma was the predominant histology (67.7%), and most patients received chemo–immunotherapy (81.6%), while 18.4% received immunotherapy alone. PD-L1 expression ≥ 1% was present in 59.2% of patients. In the overall cohort, median PFS and OS were 12 and 15 months, respectively. Median OS was 17 months in the ACEI group compared with 14 months in the non-ACEI group (log-rank p < 0.047), while median PFS was 14 months versus 11 months, respectively (p = 0.066). The survival advantage was more pronounced for OS than for PFS and remained consistent after adjustment for clinical characteristics including age, sex, ECOG performance status, smoking status, histology, treatment regimen, and PD-L1 expression. Conclusions: These findings suggest that chronic ACE inhibitor use may be associated with improved outcomes in metastatic NSCLC patients treated with immune checkpoint inhibitors.