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CTHRC1+ cancer associated-fibroblasts promotes malignant progression of bladder cancer cells via inducing an immunosuppressive tumor microenvironment
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DOI：10.3389/fimmu.2026.1898002.png)
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Abstract
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IntroductionBladder 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.MethodsCTHRC1+ 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.ResultsWe 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.ConclusionsThese findings identify CTHRC1+ CAFs as key promoters of bladder cancer progression and immune evasion; suggesting CTHRC1 as a potential prognostic biomarker for bladder cancer.
Keywords:
bladder cancer
macrophage polarization
Th2 cells
CTHRC1
cancer associated fibroblasts (CAFs)
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