Angiotensin II signaling via AT1R may promote stromal remodeling and immune exclusion in non-small cell lung cancer, suggesting AT1R blockade as a potential microenvironment-normalizing adjunct.
Does RAAS inhibition normalize the tumor microenvironment and improve outcomes in NSCLC?
RAAS inhibition may normalize the tumor microenvironment in NSCLC, but prospective biomarker-stratified studies are needed to confirm clinical benefit.
Introduction Lung cancer progression is shaped by vascular dysfunction, hypoxia, desmoplastic remodeling, and immune exclusion. Beyond its endocrine role, the renin–angiotensin–aldosterone system (RAAS) functions locally and may regulate these microenvironmental states. This review evaluates RAAS–mediated stromal and immune regulation in non–small cell lung cancer (NSCLC). Method This narrative review synthesized English-language evidence from PubMed/MEDLINE, Web of Science, Scopus, ScienceDirect, and Google Scholar through April 2026. Lung cancer studies were prioritized; evidence from other settings was included to clarify mechanisms. Results Angiotensin II signaling through the angiotensin II type 1 receptor (AT1R) in fibroblast-rich niches may promote cancer-associated fibroblast activation, extracellular matrix accumulation, solid stress, impaired perfusion, hypoxia, and CD8+ T-cell exclusion. Accordingly, AT1R blockade may function as a microenvironment-normalizing adjunct rather than a direct tumor-cell-intrinsic cytotoxic strategy. The angiotensin-converting enzyme 2/angiotensin-(1–7)/Mas receptor axis, angiotensin II type 2 receptor signaling, and mineralocorticoid receptor signaling show context- and compartment-dependent effects, while transcript abundance alone cannot establish peptide availability or receptor engagement. Clinical evidence linking RAAS inhibitors to improved outcomes, particularly during immune checkpoint inhibitor therapy, remains retrospective and susceptible to confounding. Conclusions Translation requires biomarker-stratified prospective studies demonstrating intratumoral target engagement and linking outcomes to measurable changes in matrix architecture, perfusion, hypoxia, and spatial immune organization.
Liu et al. (Wed,) conducted a review in non-small cell lung cancer (NSCLC). RAAS signaling was evaluated. Angiotensin II signaling via AT1R may promote stromal remodeling and immune exclusion in non-small cell lung cancer, suggesting AT1R blockade as a potential microenvironment-normalizing adjunct.