{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T23:28:20Z","timestamp":1793834900198,"version":"4.6.1"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"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>Periostin (POSTN), an extracellular matrix protein secreted by cancer-associated fibroblasts (CAFs), critically shapes the tumor microenvironment. While POSTN contributes to tumor progression and immune regulation by modifying the microenvironment, its direct influence on T-cell activity and antitumor immunity remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this study, single-cell and bulk RNA sequencing datasets were mined and combined with multiplex fluorescence immunohistochemistry to elucidate the role of POSTN\n                      <jats:sup>+<\/jats:sup>\n                      CAFs. Primary CAFs were isolated and fibroblast lines with\u00a0elevated POSTN expression were established to assess their direct impact on T-cells through functional assays. Transcriptome sequencing identified downstream regulatory pathways in POSTN\n                      <jats:sup>+<\/jats:sup>\n                      CAFs. A mouse peritoneal metastasis model was used to evaluate the therapeutic potential of targeting POSTN\n                      <jats:sup>+<\/jats:sup>\n                      CAFs in combination with immunotherapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Integration of single-cell transcriptomic datasets enabled the construction of a predictive model for gastric cancer peritoneal metastasis (GCPM) based on T-cell exhaustion-associated genes. POSTN was found to be primarily expressed by CAFs in GCPM tissues, with elevated levels correlating with poor clinical outcomes. Functionally, POSTN\n                      <jats:sup>+<\/jats:sup>\n                      CAFs promoted adhesion and spheroid formation by autocrine activation of the AKT-NF-\u03baB-ICAM-1 signaling pathway, facilitating peritoneal dissemination. Co-culture and\n                      <jats:italic>in vivo<\/jats:italic>\n                      experiments suggested that POSTN\n                      <jats:sup>+<\/jats:sup>\n                      CAFs may promote CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell exhaustion via ICAM-1-ETV3 signaling, resulting in diminished effector function and cytokine production. Inhibiting POSTN downstream signaling with the integrin receptor antagonist Cilengitide, especially together with immune checkpoint blockade (anti-PD-1 and anti-CTLA-4), markedly reduced T-cell exhaustion and suppressed GCPM.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our results indicate that POSTN\n                      <jats:sup>+<\/jats:sup>\n                      CAFs are pivotal in maintaining an immunosuppressive microenvironment in GCPM. POSTN may facilitates CAFs-tumor and CAFs-T-cell interactions through ICAM-1, thereby promoting metastasis and promoting immune evasion. Targeting the POSTN-ICAM-1 axis may provide a therapeutic approach to enhance immunotherapy efficacy and enhance immunotherapy outcomes in patients with GCPM.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1796080","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T05:42:20Z","timestamp":1781070140000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["POSTN+ CAFs facilitate gastric cancer peritoneal metastasis by promoting ICAM-1-dependent tumor cell adhesion and CD8+ T-cell exhaustion"],"prefix":"10.3389","volume":"17","author":[{"given":"Xin","family":"Liu","sequence":"first","affiliation":[{"name":"Department of General Surgery, Tianjin Medical University General Hospital","place":["Tianjin, 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