Telmisartan enhances anti-PD-1 efficacy in MSS colorectal cancer via modulation of PD-L1 and STAT3 signaling.

Abstract

Background: Microsatellite stable (MSS) colorectal cancer (CRC), accounting for over 85% of advanced cases, shows intrinsic resistance to immune checkpoint inhibitors due to an immunosuppressive tumor microenvironment. The renin-angiotensin system (RAS), particularly angiotensin II type 1 receptor (AT1R), has been implicated in tumor progression and immune evasion. This study investigated whether telmisartan, a selective AT1R antagonist, modulates programmed death-ligand 1 (PD-L1) expression and enhances anti-tumor immunity in MSS CRC.

Methods: Mismatch repair (MMR) protein expression was characterized in human (SW480, HT29, HCT116) and murine (CT26) CRC cell lines. The effects of telmisartan on cell viability, PD-L1 expression, STAT3 signaling, and migration were evaluated using Cell Counting Kit-8 (CCK-8), Western blotting, and Transwell assays. A CT26 tumor model in BALB/c mice was used to assess therapeutic efficacy alone or combined with pembrolizumab, with immunohistochemical analysis of tumor-infiltrating lymphocytes. Public transcriptomic analysis of The Cancer Genome Atlas (TCGA) CRC data and immune infiltration analysis using the CIBERSORT (Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts) algorithm were further performed.

Results: Telmisartan (10-20 μM) reduced PD-L1 expression in both MSS and MSI-H CRC cell lines without significant cytotoxicity. It was associated with increased signal transducer and activator of transcription 3 (STAT3) phosphorylation and reduced cell migration. In vivo, telmisartan inhibited tumor growth, while the combination with pembrolizumab resulted in enhanced antitumor efficacy. These effects were accompanied by increased infiltration of CD3⁺, CD4⁺, and CD8⁺ T cells. Transcriptomic analysis demonstrated positive correlations among AGTR1, STAT3, and CD274 expression, while CIBERSORT analysis revealed AGTR1-associated alterations in immune cell infiltration.

Conclusions: Telmisartan may remodel the tumor immune microenvironment, potentially through modulation of PD-L1 expression associated with STAT3 signaling, thereby enhancing the response of MSS CRC to immune checkpoint blockade. These findings suggest that telmisartan could serve as a potential immunotherapy adjuvant for MSS CRC.