Renin-angiotensin system inhibitors and immunotherapy outcomes in lung cancer: a systematic review and meta-analysis with complementary transcriptomic analyses.

Background: The tumor microenvironment has emerged as an important determinant of response to immune checkpoint inhibitors (ICIs), with increasing attention directed toward stromal components such as cancer-associated fibroblasts (CAFs). Experimental evidence suggests that renin-angiotensin system (RAS) signaling may participate in stromal remodeling and immune regulation, raising interest in whether RAS inhibitors could influence immunotherapy outcomes. However, clinical findings remain inconsistent and the extent to which reported associations reflect biological effects rather than study-level bias remains uncertain. This study aimed to systematically evaluate the association between concomitant RAS inhibitor use and survival outcomes in lung cancer patients receiving ICIs while interpreting the findings within a tumor microenvironment-oriented conceptual framework. Methods: PubMed and Embase were searched from database inception through February 2026. Eligible studies included lung cancer patients receiving ICIs and reported hazard ratios (HRs) for overall survival (OS) and/or progression-free survival (PFS) according to concomitant RAS inhibitor exposure. Random-effects meta-analyses were performed to pool effect estimates. Publication bias and potential small-study effects were evaluated using Egger's regression and explored using Precision-Effect Test and Precision-Effect Estimate with Standard Error (PET-PEESE). Results: Thirteen eligible publications involving 46,618 patients were included. Conventional random-effects analyses suggested improved OS (HR 0.74, 95% CI 0.64-0.86) and PFS (HR 0.81, 95% CI 0.68-0.96) among RAS inhibitor users. However, substantial funnel plot asymmetry and significant Egger's test results for OS indicated possible small-study effects. Exploratory PET-PEESE analyses attenuated the observed associations toward the null (adjusted OS HR 0.99, 95% CI 0.96-1.02; adjusted PFS HR 1.04, 95% CI 0.85-1.27). Subgroup analyses suggested possible heterogeneity across histological and regional categories, although these findings should be interpreted cautiously. Conclusions: Current evidence does not indicate a consistent survival advantage associated with concomitant RAS inhibitor use in unselected lung cancer populations treated with ICIs. The discrepancy between conventional pooling and exploratory bias-adjusted analyses suggests that the observed survival advantage may be partially attributable to small-study effects and residual confounding rather than a reproducible treatment-enhancing effect. Rather than supporting routine clinical use of RAS inhibitors to enhance immunotherapy efficacy, these findings support further biomarker-informed investigation into stromal and tumor microenvironment contexts that may contribute to differential treatment responses. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420261369330.