AGTR1 signaling contributes to tumor immunity and therapy response in non-small cell lung cancer

Angiotensin II receptor type 1 (AGTR1) has emerged as a potential modulator of the tumor microenvironment, yet its role in the immunotherapy response in non-small cell lung cancer (NSCLC) remains unclear. We performed a comprehensive analysis using bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) datasets. Functional validation included IHC for AGTR1 and phospho-SMAD2/3 co-localization. The clinical impact of angiotensin receptor blocker (ARB) use was assessed in patients receiving immune checkpoint blockade (ICB) alone or combined with chemo-immunotherapy. AGTR1-high expression in NSCLC was associated with pronounced pathway modulation, including significant upregulation of TGF-β, etc. scRNA-seq analysis revealed that AGTR1 was predominantly localized in cancer-associated fibroblasts (CAFs). IHC validation in NSCLC specimens (n = 14) demonstrated a strong correlation between stromal AGTR1 and phospho-SMAD2/3 expression and ARB-treated patients showed significantly reduced stromal AGTR1 and pSMAD2/3 expression. Clinically, ARB treatment showed no benefit in ICB monotherapy but significantly improved PFS in chemo-immunotherapy (HR = 0.70, p = 0.01), especially in non-squamous (non-Sq) histology with PD-L1≥1% (HR = 0.52, p = 0.01). AGTR1 is predominantly expressed in CAFs and is suggestive of a correlation with TGF-β-related immunosuppressive features in NSCLC. The combination of ARB with chemo-immunotherapy may enhance therapeutic efficacy through targeting that axis in CAFs, specifically in non-Sq NSCLC patients.