Simple SummaryBiliary tract cancers (BTCs), comprising cancers of the bile ducts (cholangiocarcinoma) as well as gallbladder cancers, continue to be challenging to treat. Cancer immunotherapy strategies harness the immune system to help to attack cancer cells. A number of immunotherapy approaches have been or are currently being studied in BTCs, including immune checkpoint inhibitors (ICIs) that block immune-suppressing signals, immune-stimulating agonists, modified T cells that target tumor components (CAR-T), and cancer vaccines. Here, we discuss the use of immunotherapy on its own or in combination with (1) chemotherapy, (2) drugs that target specific tumor proteins, or (3) blood-vessel-targeted treatments. At present, the combination of an ICI with chemotherapy is established as the standard of care, first-line treatment for BTCs that have spread to distant parts of the body or that cannot be removed surgically. Ongoing work will help to explore further approaches and scenarios in which immunotherapy may positively impact the management of BTCs.AbstractBiliary tract cancers (BTCs), comprising intrahepatic, perihilar, and distal cholangiocarcinoma as well as gallbladder adenocarcinoma, continue to be challenging to manage. Conventional chemotherapy regimens for advanced disease are limited in both options and benefits, and more effective perioperative regimens are also needed. Over the last decade, immunotherapy has had a profound impact on the management of many solid tumor types, particularly in using immune checkpoint inhibition to enable a tumor-directed T cell response. Immunotherapy administered on its own has had limited utility in BTCs, in part due to a hostile immune microenvironment and the relative infrequency of biomarker-based tumor-agnostic indications for immunotherapy. However, immunotherapy in conjunction with chemotherapy, molecularly targeted therapies, and/or anti-angiogenic therapies has gained traction, supported by evidence that these agents can impart favorable immunomodulatory effects on the tumor microenvironment. The TOPAZ-1 trial led to the first BTC-specific immunotherapy approval, establishing the combination of durvalumab with gemcitabine and cisplatin as the preferred first-line treatment for advanced or metastatic disease. Recently, the KEYNOTE-966 trial showed positive results for the combination of pembrolizumab with gemcitabine and cisplatin in the same setting, adding further evidence for the addition of immune checkpoint inhibition to the standard chemotherapy backbone. Meanwhile, advances in the molecular profiling of BTCs has contributed to the recent proliferation of molecularly targeted therapeutics for the subset of BTCs harboring alterations inIDH1,FGFR2, MAP kinase signaling,HER2, and beyond, and there has been great interest in investigating combinations of these agents with immunotherapy. Emerging immunotherapy strategies beyond immune checkpoint inhibition are also being studied in BTCs, and these include immunostimulatory receptor agonists, Wnt signaling modulators, adoptive cell therapy, and cancer vaccines. A large number of trials are underway to explore promising new combinations and immune-targeted strategies, offering opportunities to expand the role of immunotherapy in BTC management in the near future.