{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T17:47:42Z","timestamp":1793468862822,"version":"4.5.0"},"reference-count":35,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"unspecified","delay-in-days":28,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Zhejiang Provincial Medical and Health Science and Technology Plan","award":["2025KY556"],"award-info":[{"award-number":["2025KY556"]}]},{"name":"Zhejiang Provincial Medical and Health Science and Technology Plan","award":["2026781539"],"award-info":[{"award-number":["2026781539"]}]},{"name":"Zhejiang Provincial Medical and Health Science and Technology Plan","award":["WKJ-ZJ-2516"],"award-info":[{"award-number":["WKJ-ZJ-2516"]}]},{"name":"Zhejiang Provincial Natural Science Foundation","award":["Y24H290050"],"award-info":[{"award-number":["Y24H290050"]}],"id":[{"id":"https:\/\/ror.org\/04aqat463","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100022963","name":"Key Research and Development Program of Zhejiang Province","doi-asserted-by":"publisher","award":["2024C03030"],"award-info":[{"award-number":["2024C03030"]}],"id":[{"id":"10.13039\/100022963","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Traditional Chinese Medicine Science and Technology Program Project of Zhejiang Province","award":["2025ZL204"],"award-info":[{"award-number":["2025ZL204"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32570870"],"award-info":[{"award-number":["32570870"]}],"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":["82403257"],"award-info":[{"award-number":["82403257"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Joint TCM Science & Technology Projects of National Demonstration Zones for Comprehensive TCM Reform","award":["GZY-KJS-ZJ-2026-035"],"award-info":[{"award-number":["GZY-KJS-ZJ-2026-035"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,9,10]]},"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Most colorectal cancers (CRCs) patients with microsatellite stability (MSS) have minimal benefit from immune checkpoint inhibitor monotherapy, and even after PD-1\/PD-L1 blockade, T cell function remains inadequately restored, highlighting the importance of PD-1 downstream signaling events. SHP-2 is a critical effector of PD-1 downstream signaling and plays a key role in establishing the immunosuppressive tumor microenvironment in CRC. Gut microbial metabolites are emerging as regulators of anti-tumor immunity, but their role in modulating the PD-1\/SHP-2 interaction remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We established a split-luciferase complementation screening system based on the PD-1\/SHP-2 interaction and systematically screened a library of human gut microbial metabolites (n=480). The effect of candidate metabolites on T cell function was assessed\n                      <jats:italic>in vitro<\/jats:italic>\n                      using flow cytometry, confocal microscopy, and cell viability assays. Using a mouse colon cancer model, we further investigated the role of taurocholic acid (TCA) and glycodeoxycholic acid (GDCA) in the tumorigenesis and immunotherapy of CRC. Finally, the clinical relevance of metabolite-producing bacterium was examined in tumor specimens from CRC patients (n=53) using fluorescence\n                      <jats:italic>in situ<\/jats:italic>\n                      hybridization and real-time PCR assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified the conjugated bile acids TCA and GDCA as enhancers of the PD-1\/SHP-2 interaction. Mechanistically, TCA and GDCA stabilized the PD-1\/SHP-2 complex through an allosteric mechanism by promoting PD-1 phosphorylation. Functionally, two metabolites suppressed CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell activation, proliferation, and cytotoxicity in a PD-1\/SHP-2-dependent manner, thereby accelerating tumor progression\n                      <jats:italic>in vivo<\/jats:italic>\n                      . Conversely, pharmacological depletion of TCA and GDCA using the bile acid sequestrant cholestyramine (CHO) effectively reversed their immunosuppressive effect and synergized with anti-PD-1 antibody therapy to inhibit the tumorigenesis of CRC. Clinical sample analysis revealed that the abundance of\n                      <jats:italic>Clostridium scindens<\/jats:italic>\n                      , the primary bacterial source of TCA and GDCA, was inversely correlated with CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell infiltration in tumor tissues from CRC patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study reveals a \u201cBile acid-associated metabolites-Immune checkpoint\u201d regulatory axis that drives immunosuppression in CRC. The identification of TCA and GDCA as endogenous enhancers of PD-1 signaling provides a mechanistic rationale for targeting these metabolites to overcome immunotherapy resistance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2026-015554","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:55:11Z","timestamp":1790693711000},"page":"e015554","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Screening of known gut microbiome-derived metabolites in anti-tumor immunity of colorectal cancer"],"prefix":"10.1136","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8975-1792","authenticated-orcid":false,"given":"Xinan","family":"Zhang","sequence":"first","affiliation":[{"name":"Cancer Center, Department of Medical Oncology, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People\u2019s 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