{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T06:30:43Z","timestamp":1786516243808,"version":"build-2736575974"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:sup>+<\/jats:sup>\n                      CAFs subsets to bladder cancer progression remains poorly defined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      CTHRC1\n                      <jats:sup>+<\/jats:sup>\n                      CAFs were successfully isolated from human patient specimens and mouse xenograft models. To systematically evaluate the function of CTHRC1\n                      <jats:sup>+<\/jats:sup>\n                      CAFs in bladder cancer, a comprehensive suite of assays was employed, including CCK-8, Transwell, murine xenograft models, ELISA, flow cytometry, and Western blotting.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that CTHRC1 was predominantly expressed in CAFs, and CTHRC1\n                      <jats:sup>+<\/jats:sup>\n                      CAFs promoted cell growth, migration and invasion of bladder cancer cells both\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      . Moreover, CTHRC1\n                      <jats:sup>+<\/jats:sup>\n                      CAFs fostered an immunosuppressive tumor microenvironment by driving M2 macrophage polarization and Th2 differentiation, which subsequently suppressed the antitumor activity of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells. Mechanistically, CTHRC1 activated the PI3K\/Akt\/NF-\u03baB pathway in CAFs and induced the secretion of various immunomodulatory cytokines, which regulated M2 macrophage polarization and Th2 differentiation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These findings identify CTHRC1\n                      <jats:sup>+<\/jats:sup>\n                      CAFs as key promoters of bladder cancer progression and immune evasion, suggesting CTHRC1 as a potential prognostic biomarker for bladder cancer.\n                    <\/jats:p>\n                  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