CTHRC1+ cancer associated-fibroblasts promotes malignant progression of bladder cancer cells via inducing an immunosuppressive tumor microenvironment.

INTRODUCTION: Bladder cancer remains a therapeutic challenge due to its high recurrence and metastasis rates. Cancer-associated fibroblasts (CAFs) are recognized as pivotal regulators of the tumor microenvironment (TME), however the specific contribution of CTHRC1+ CAFs subsets to bladder cancer progression remains poorly defined. METHODS: CTHRC1+ CAFs were successfully isolated from human patient specimens and mouse xenograft models. To systematically evaluate the function of CTHRC1+ CAFs in bladder cancer, a comprehensive suite of assays was employed, including CCK-8, Transwell, murine xenograft models, ELISA, flow cytometry, and Western blotting. RESULTS: We found that CTHRC1 was predominantly expressed in CAFs, and CTHRC1+ CAFs promoted cell growth, migration and invasion of bladder cancer cells both in vitro and in vivo. Moreover, CTHRC1+ CAFs fostered an immunosuppressive tumor microenvironment by driving M2 macrophage polarization and Th2 differentiation, which subsequently suppressed the antitumor activity of CD8+ T cells. Mechanistically, CTHRC1 activated the PI3K/Akt/NF-κB pathway in CAFs and induced the secretion of various immunomodulatory cytokines, which regulated M2 macrophage polarization and Th2 differentiation. CONCLUSIONS: These findings identify CTHRC1+ CAFs as key promoters of bladder cancer progression and immune evasion, suggesting CTHRC1 as a potential prognostic biomarker for bladder cancer.