{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T21:39:49Z","timestamp":1789508389808,"version":"build-2803163510"},"reference-count":59,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"unspecified","delay-in-days":8,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"shanghai Pujiang Program","award":["23PJ1401400"],"award-info":[{"award-number":["23PJ1401400"]}]},{"name":"Project of Science and Technology of Xiamen City","award":["3502Z20224015"],"award-info":[{"award-number":["3502Z20224015"]}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2024J011445"],"award-info":[{"award-number":["2024J011445"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82002527"],"award-info":[{"award-number":["82002527"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82573106"],"award-info":[{"award-number":["82573106"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,2,9]]},"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Peritoneal metastasis (PM) is one of the most challenging clinical problems in gastric cancer (GC), largely due to its high recurrence rate and poor response to current therapies. Increasing evidence indicates that remodeling of the extracellular matrix (ECM) plays an important role in therapeutic failure. However, how specific stromal\u2013immune interactions contribute to PM heterogeneity and immunotherapy resistance remains unclear. In this study, we investigated how ECM composition\u2014particularly the accumulation of hyaluronic acid (HA)\u2014influences the immune microenvironment and therapeutic responses in GC-associated PM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We combined histopathological assessment, analyses of patient-derived specimens, single-cell transcriptomic profiling, and murine models of PM to delineate ECM remodeling patterns and immune cell dynamics in therapy-sensitive and therapy-resistant lesions. In addition, functional assays and pharmacological approaches were used to examine HA\u2013CD44 signaling and its impact on CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell differentiation and responsiveness to immune checkpoint blockade.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Therapy-sensitive PM lesions were characterized by enrichment of elastic fibers, whereas therapy-resistant lesions showed collagen accumulation. Notably, HA deposition emerged as a key feature distinguishing these ECM states and was closely associated with differential therapeutic outcomes. Elevated HA levels activated CD44-dependent signaling in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells, driving regulatory T cell (Treg) differentiation through a CD44\u2013IQGAP1\u2013RAC1\u2013SMAD3 signaling pathway and thereby establishing an immunosuppressive microenvironment. Importantly, pharmacological inhibition of CD44 reduced Treg expansion and markedly enhanced the antitumor efficacy of anti-PD-1 therapy in murine PM models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings identify HA\u2013CD44 signaling as a critical link between ECM remodeling and immune evasion in GC PM. Targeting ECM-driven immunosuppressive mechanisms may represent a promising strategy to overcome therapeutic resistance and improve the efficacy of immunotherapy in this aggressive disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-014179","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T14:40:21Z","timestamp":1773067221000},"page":"e014179","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Hyaluronic acid-CD44 signaling defines therapeutic resistance and immunosuppressive microenvironment in peritoneal metastasis of gastric cancer"],"prefix":"10.1136","volume":"14","author":[{"given":"Junjie","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Surgery, Zhongshan Hospital, Fudan University, Shanghai, China"},{"name":"Gastric Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 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