{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T23:20:10Z","timestamp":1793056810014,"version":"4.5.0"},"reference-count":49,"publisher":"BMJ","issue":"12","license":[{"start":{"date-parts":[[2025,12,21]],"date-time":"2025-12-21T00:00:00Z","timestamp":1766275200000},"content-version":"unspecified","delay-in-days":20,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82103432"],"award-info":[{"award-number":["82103432"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82373143"],"award-info":[{"award-number":["82373143"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,12,1]]},"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The immunomodulatory roles of cancer-associated fibroblasts (CAFs) in gastric cancer have been increasingly recognized. This study aimed to identify specific CAF subpopulations and to elucidate the mechanisms underlying their immunosuppressive effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We developed a single-cell RNA sequencing (scRNA-seq) protocol to enrich CAFs and matched normal fibroblasts (NFs) from stomach tissues. Bioinformatics analyses, along with in vitro and in vivo experiments, were performed to functionally validate a distinct CAF subset.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We profiled 8,322 high-quality fibroblasts from nine patient-matched tumor and adjacent normal tissue pairs. A unique CAF subset,\n                      <jats:italic>CD146<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      CAFs, was identified.\n                      <jats:italic>CD146<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      CAFs were significantly enriched in the tumor microenvironment and associated with poor survival and M2-like macrophage infiltration. Tumor cells promoted\n                      <jats:italic>CD146<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      CAFs expansion via JAG1-NOTCH3 and LGALS3-CD146 signaling. Mechanistically, NOTCH3 acted as a master regulator in\n                      <jats:italic>CD146<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      CAFs. Tumor cell-derived JAG1 engaged NOTCH3 on\n                      <jats:italic>CD146<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      CAFs, which triggered PI3K\/AKT-mediated CD146 transcription and enhanced COL4A1 secretion. Functionally,\n                      <jats:italic>CD146<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      CAF-derived COL4A1 bound macrophage CD44\/IL7R to drive macrophage M2-like polarization, thereby suppressing CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell function. Therapeutic blockade of CD146 or COL4A1 in vivo impaired M2 polarization, reinvigorated CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell activity, and restrained tumor growth.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our findings underscore the pivotal role of\n                      <jats:italic>CD146<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      CAFs in shaping an immunosuppressive microenvironment and highlight\n                      <jats:italic>CD146<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      CAFs\u2009and COL4A1 as promising candidates for targeted therapy in gastric cancer.\n                    <\/jats:p>\n                  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