{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T12:17:20Z","timestamp":1788351440159,"version":"build-2803163510"},"reference-count":52,"publisher":"BMJ","issue":"8","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"unspecified","delay-in-days":5,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"the Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Cancer","award":["2020B121201004"],"award-info":[{"award-number":["2020B121201004"]}]},{"name":"the Key Clinical Technique of Guangzhou","award":["2023P-ZD01"],"award-info":[{"award-number":["2023P-ZD01"]}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82272062"],"award-info":[{"award-number":["82272062"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the Key Areas Research and Development Programs of Guangdong Province","award":["2023B1111050009"],"award-info":[{"award-number":["2023B1111050009"]}]},{"name":"Hospital Talent Program Supporting Grant","award":["2025GJZCJH001"],"award-info":[{"award-number":["2025GJZCJH001"]}]},{"name":"the Development Project of the Gastrointestinal Oncology Research Institute at Nanfang Hospital","award":["J1010171102"],"award-info":[{"award-number":["J1010171102"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,7,29]]},"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The tumor microbiota critically shapes responses to immunotherapy; however, the mechanisms by which specific microbial species drive immune checkpoint blockade (ICB) resistance in gastric cancer (GC) remain poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Streptococcus anginosus<\/jats:italic>\n                      enrichment was assessed in ICB-unresponsive GC tissues from patients and multiple preclinical models. Orthotopic, subcutaneous, and germ-free mono-colonized mouse models were employed to evaluate the impact of\n                      <jats:italic>S. anginosus<\/jats:italic>\n                      on antitumor immunity and programmed cell death protein 1 (PD-1) blockade efficacy. Integrated multi-omics analyses were performed to identify microbiota-derived metabolites, and mechanistic studies investigated their effects on CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell function. Therapeutic targeting of integrin \u03b12 (ITGA2) was tested to assess restoration of cytotoxic T-cell activity and sensitization to PD-1 blockade.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>S. anginosus<\/jats:italic>\n                      was markedly enriched in ICB-non-responsive GC tissues. Colonization with\n                      <jats:italic>S. anginosus<\/jats:italic>\n                      impaired antitumor immunity and promoted PD-1 blockade resistance by suppressing CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell effector function. Multi-omics analyses identified kynurenic acid (KA) as a microbiota-derived metabolite selectively enriched following\n                      <jats:italic>S. anginosus<\/jats:italic>\n                      colonization. KA induced ITGA2 expression and inhibited an mTOR-dependent signaling cascade, sustaining cathepsin V expression and attenuating interferon-\u03b3 and granzyme B production in CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells. Therapeutic inhibition of ITGA2 restored CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell cytotoxicity and sensitized tumors to PD-1 blockade.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      A microbiota-metabolite-immune signaling axis involving\n                      <jats:italic>S. anginosus<\/jats:italic>\n                      , KA, and ITGA2 drives immunotherapy resistance in GC. Therapeutic inhibition of ITGA2 represents a potential strategy to overcome ICB resistance in GC.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2026-015172","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T11:25:23Z","timestamp":1786015523000},"page":"e015172","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["<i>Streptococcus anginosus<\/i>\n                    -associated kynurenic acid drives PD-1 blockade resistance through an ITGA2-mTOR-CTSV axis in gastric cancer"],"prefix":"10.1136","volume":"14","author":[{"given":"Yingxin","family":"Ren","sequence":"first","affiliation":[{"name":"Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of 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