{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T03:17:17Z","timestamp":1793157437579,"version":"4.5.0"},"reference-count":32,"publisher":"BMJ","issue":"11","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"unspecified","delay-in-days":25,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Guangdong Provincial Key Laboratory of Immune Regulation and Immune Therapy","award":["G822343169"],"award-info":[{"award-number":["G822343169"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82103448"],"award-info":[{"award-number":["82103448"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Guangdong Natural Science Foundation","doi-asserted-by":"crossref","award":["2023A1515010322"],"award-info":[{"award-number":["2023A1515010322"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,10,23]]},"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Intrahepatic cholangiocarcinoma (ICC) offers limited opportunities for surgical treatment, and advanced-stage patients exhibit poor responses to immunotherapy. Therefore, the exploration of new therapeutic strategies is of paramount importance. The farnesoid X receptor (FXR) is a nuclear receptor that has been reported to regulate immune cells in recent years. However, whether FXR can regulate CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells to affect tumor development remains unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The function of FXR in CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell-mediated antitumor immunity was assessed using spontaneous murine ICC models in systemic\n                      <jats:italic>Nr1h4<\/jats:italic>\n                      -knockout, and T cell-specific conditional knockout mice, with immune phenotyping performed by multicolor flow cytometry. The tumor antigen-specific CD8\n                      <jats:sup>+<\/jats:sup>\n                      T response was tracked by tetramer staining and adoptive transfer of OT-1 T cells. The regulatory mechanism of FXR was confirmed using RNA sequencing, Chromatin Immunoprecipitation sequencing (ChIP-seq), Chromatin Immunoprecipitation polymerase chain reaction (ChIP-PCR), and luciferase reporter assays. The translational therapeutic potential was evaluated by administration of the FXR inhibitor ursodeoxycholic acid (UDCA), both as monotherapy and in combination with anti-programmed death-ligand 1 (PD-L1) blockade, in murine models and ex vivo using patient-derived tumor fragments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      FXR was specifically overexpressed in exhausted CD8\n                      <jats:sup>+<\/jats:sup>\n                      tumor-infiltrating lymphocytes in both human and murine ICC. FXR ablation enhanced CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell effector function, proliferation, and stem-like progenitor capacity, leading to potent tumor control. Mechanistically, FXR transcriptionally upregulated the exhaustion marker LAG3 by directly binding to its promoter. Pharmacological inhibition of FXR with UDCA reversed T-cell exhaustion, and synergized with anti-PD-L1 therapy to significantly suppress tumor growth and enhance tumor cell apoptosis in murine models and human ICC ex vivo cultures.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Together, these data identify FXR as an immune checkpoint and support repurposing UDCA for ICC immunotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-012259","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T20:35:13Z","timestamp":1764362113000},"page":"e012259","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["FXR-mediated antigen-specific CD8\n                    <sup>+<\/sup>\n                    T cell enhances antitumor immunity in intrahepatic cholangiocarcinoma"],"prefix":"10.1136","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2905-3283","authenticated-orcid":false,"given":"Shanshan","family":"Liu","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixing","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Hepatic Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhao","family":"Zheng","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyuan","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Hepatic Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shusen","family":"Ye","sequence":"additional","affiliation":[{"name":"Institute of Immunological Innovation and Translation, Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Texi","family":"Liang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, 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