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

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.