{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T23:54:54Z","timestamp":1793145294135,"version":"4.5.0"},"reference-count":39,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"unspecified","delay-in-days":25,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Science and Technology Program of Guangzhou","award":["2025A04J4442"],"award-info":[{"award-number":["2025A04J4442"]}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2024A1515011916"],"award-info":[{"award-number":["2024A1515011916"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2025A1515010075"],"award-info":[{"award-number":["2025A1515010075"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171944"],"award-info":[{"award-number":["82171944"]}],"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":["82202162"],"award-info":[{"award-number":["82202162"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"2024 Sun Yat-sen Pilot Scientific Research Fund","award":["YXQH202404"],"award-info":[{"award-number":["YXQH202404"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,6,17]]},"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Incomplete thermal ablation (iTA) for hepatocellular carcinoma (HCC) fosters an immunosuppressive microenvironment driving local recurrence, yet the metabolic cues linking tissue injury to immune evasion remain undefined. Bile acids, particularly lithocholic acid (LCA), are elevated post-ablation, but their functional role in HCC recurrence is unknown. Here, we investigate whether LCA accumulation after iTA promotes tumor recurrence by suppressing antitumor immunity and identify the underlying molecular mechanism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Orthotopic and subcutaneous HCC models were subjected to iTA. Bile acid metabolomics, multicolor flow cytometry, and immunofluorescence staining were performed. Human residual HCC specimens were analyzed for vitamin D receptor (VDR) expression, macrophage polarization and invariant natural killer T (iNKT) cell density. For mechanistic studies, tumor-associated macrophage (TAM)-specific conditional knockdown of\n                      <jats:italic>Vdr<\/jats:italic>\n                      or\n                      <jats:italic>Socs3<\/jats:italic>\n                      , along with iNKT cell co-culture systems, were employed. The therapeutic efficacy of tauroursodeoxycholic acid (TUDCA), a bile acid modulator that counteracts LCA-mediated effects, was evaluated in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      iTA markedly elevated intrahepatic LCA levels, which correlated with M2-like TAM polarization and reduced iNKT tumor infiltration. LCA functioned as a VDR agonist in TAMs, transcriptionally upregulating suppressor of cytokine signaling 3 (SOCS3) and suppressing C-X-C motif chemokine ligand 16 (CXCL16). This VDR-SOCS3-CXCL16 axis was necessary and sufficient for impaired iNKT chemotaxis, as genetic ablation of VDR or SOCS3 in TAMs restored CXCL16 secretion. Conversely, LCA treatment inhibited iNKT cell chemotaxis and interferon-\u03b3 secretion, which were restored by exogenous CXCL16 supplementation. In human residual HCC, post-ablation tissues exhibited M2-like TAM polarization, and VDR\n                      <jats:sup>+<\/jats:sup>\n                      TAM density inversely correlated with intratumoral iNKT cells. Pharmacologically, TUDCA remodeled the bile acid pool, suppressed LCA-VDR signaling, reinstated CXCL16 expression, reprogrammed TAMs toward an M1-like phenotype, and significantly inhibited post-ablation tumor growth.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We identify a hitherto unknown metabolic-immune checkpoint: iTA-induced LCA activates macrophage VDR, triggering SOCS3-mediated epigenetic suppression of CXCL16 and evading iNKT surveillance. TUDCA resets this checkpoint by restoring CXCL16 expression and iNKT function. Thus, targeting this axis with TUDCA represents a readily translatable adjunctive strategy to abrogate post-ablation HCC recurrence.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2026-015177","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T07:35:19Z","timestamp":1782718519000},"page":"e015177","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Lithocholic acid-activated VDR in macrophages promotes HCC recurrence post-ablation via SOCS3-mediated suppression of CXCL16"],"prefix":"10.1136","volume":"14","clinical-trial-number":[{"clinical-trial-number":"nct07064668","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2992-4437","authenticated-orcid":false,"given":"Rumei","family":"Li","sequence":"first","affiliation":[{"name":"Department of Ultrasound, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, 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Guangzhou, Guangdong, China"},{"name":"Sun Yat-sen University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China"},{"name":"Sun Yat-sen University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuxia","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China"},{"name":"Sun Yat-sen University, Guangzhou, Guangdong, China"},{"name":"The Third People\u2019s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China"},{"name":"Sun Yat-sen University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8181-8282","authenticated-orcid":false,"given":"Wenyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China"},{"name":"Sun Yat-sen University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2331-5713","authenticated-orcid":false,"given":"Baoming","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China"},{"name":"Sun Yat-sen University, Guangzhou, Guangdong, 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The role of the sodium-taurocholate cotransporting polypeptide (NTCP) and of the bile salt export pump (BSEP) in physiology and pathophysiology of bile formation. Handb Exp Pharmacol 2011;205\u201359. doi:10.1007\/978-3-642-14541-4_5","DOI":"10.1007\/978-3-642-14541-4_5"},{"key":"2026062900351336000_14.6.e015177.39","doi-asserted-by":"publisher","DOI":"10.2133\/dmpk.18.33"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2026-015177","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T07:35:30Z","timestamp":1782718530000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2026-015177"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6]]},"references-count":39,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6,28]]},"published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1136\/jitc-2026-015177"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2026-015177","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6]]}}}