{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:12:25Z","timestamp":1788783145572,"version":"build-2803163510"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Biliary tract cancers (BTCs) are aggressive, molecularly heterogeneous malignancies, and most patients present with unresectable or metastatic disease at diagnosis. For more than a decade, gemcitabine\u2013platinum chemotherapy served as the first-line standard of care, with only modest survival benefit. The phase 3 TOPAZ-1 and KEYNOTE-966 trials have now established chemoimmunotherapy with immune checkpoint inhibitors as the new standard front-line regimen, and the phase 2 IMbrave151 trial is evaluating whether adding antiangiogenic therapy provides further benefit. Nonetheless, only a minority of patients derive durable clinical benefit from immunotherapy. Conventional predictive biomarkers\u2014deficient mismatch repair or high microsatellite instability, tumor mutational burden, and PD-L1 expression\u2014have limited discriminatory value in BTC, largely because of profound intratumoral heterogeneity. Emerging biomarkers and composite multi-feature models show greater promise for refining patient stratification. Investigational modalities, including therapeutic cancer vaccines, chimeric antigen receptor T cells, and tumor-infiltrating lymphocyte therapy, have shown preliminary antitumor activity but require validation in larger cohorts. Multiple combination regimens aimed at reversing the immunosuppressive tumor microenvironment are under active investigation, and disease-specific protocols for managing hepatobiliary immune-related adverse events remain an unmet clinical need. In this review, we synthesize the latest evidence on biomarkers, clinical trials, combination strategies, cellular therapies, and safety management for immunotherapy in advanced BTC, and we highlight persistent challenges and future research directions.<\/jats:p>","DOI":"10.3389\/fphar.2026.1927523","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T11:46:20Z","timestamp":1788781580000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunotherapy in advanced biliary tract cancer: current status and future directions"],"prefix":"10.3389","volume":"17","author":[{"given":"Wu","family":"Lv","sequence":"first","affiliation":[{"name":"Department of International Medical Services (Surgical Ward), Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital and Institute","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengjia","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Radiology, The Fourth Affiliated Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Fuxin Traditional Chinese Medicine Hospital","place":["Fuxin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilin","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of International Medical Services (Surgical Ward), Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital and Institute","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Surgery, Donggang Hospital of Traditional Chinese Medicine","place":["Donggang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoquan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of International Medical Services (Surgical Ward), Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital and Institute","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"S1382","DOI":"10.1016\/j.annonc.2024.09.034","article-title":"First-line pemigatinib plus pembrolizumab versus chemotherapy in patients with FGFR2-rearranged advanced or metastatic cholangiocarcinoma: primary results from the phase 3 FIGHT-302 trial","volume":"35","author":"Abou-Alfa","year":"2024","journal-title":"Ann. 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