{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T06:07:52Z","timestamp":1788847672092,"version":"build-2803163510"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"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>Background<\/jats:title>\n                    <jats:p>\n                      Key features of gastric cancer (GC) include its aggressive nature, high metastatic capability, and a tendency for relapse. While 5-fluorouracil (5-FU) remains a cornerstone of GC treatment, its efficacy is substantially undermined by the emergence of acquired drug resistance. Carnosic acid (CA) has antitumor and immunomodulatory potential, but its role in 5-FU-resistant GC remains unclear. This study investigated whether CA enhances 5-FU sensitivity and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell-mediated antitumor immunity by regulating the CXCL12\/CXCR7 axis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The effects of CA combined with 5-FU on cell viability, proliferation, apoptosis, migration, invasion, and EMT-related features were evaluated using 5-FU-sensitive and 5-FU-resistant GC cell models and MFC\/MFC-R mouse GC models. CXCR7 overexpression, co-immunoprecipitation, immunofluorescence, and Western blotting were performed to examine CXCL12\/CXCR7-axis regulation. GC cell\/CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell co-culture, subcutaneous tumor, lung metastasis, anti-PD-L1 combination therapy, and safety models were further used for validation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      5-FU-resistant GC cells showed reduced drug sensitivity and enhanced malignant phenotypes. CA plus 5-FU suppressed proliferation, migration, invasion, and EMT, while promoting apoptosis. Mechanistically, CA restored 5-FU sensitivity by inhibiting aberrant CXCL12\/CXCR7-axis activation, whereas CXCR7 overexpression partially reversed these effects. The combined treatment also enhanced CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell proliferation, cytotoxicity, and IFN-\u03b3 and Granzyme B expression, reduced immunosuppression-associated molecules, inhibited tumor growth and lung metastasis, potentiated anti-PD-L1 efficacy, and caused no obvious systemic toxicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      CA enhances 5-FU sensitivity, suppresses EMT and metastasis-associated phenotypes, and improves CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell-mediated antitumor immunity in resistant GC by targeting the CXCL12\/CXCR7 axis.\n                    <\/jats:p>\n                  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