Chan, Stephen LStephen LChanLamarca, AngelaAngelaLamarcaCHIUN HSUMoreno, VictorVictorMorenoChan, Landon LLandon LChanKeenan, Bridget PBridget PKeenan2026-01-202026-01-202026-01https://scholars.lib.ntu.edu.tw/handle/123456789/735486The treatment of hepatobiliary cancers has advanced rapidly, with novel approaches under active development. Current drug development can be classified into two primary strategies, based on their underlying mechanisms of action. The first focuses on novel therapies targeting the immune system beyond conventional immune checkpoints like programmed death-1 and cytotoxic T-lymphocyte-associated protein 4. This includes antibodies targeting new immune checkpoints and cytokines involved in tumour immune response regulation. Phase II and III clinical trials are exploring combinations of these antibodies with approved immunotherapy regimens. Cellular therapies, including chimeric antigen receptor-T cells and tumour-infiltrating lymphocytes, are also being tested in early clinical studies for hepatocellular carcinoma (HCC) and biliary tract cancer (BTC). Advances in antibody engineering have also enabled the design of bispecific T-cell engagers. The second direction addresses new targets or revised approaches to traditionally undruggable targets, such as peroxisome proliferator-activated receptor-α, Kirsten rat sarcoma viral oncogene, histone deacetylase, and β-catenin. Successful in other cancers, antibody-drug conjugates expressing human epidermal growth factor receptor-2 or nectin-4 are also being developed for BTC. Notably, the classification of these advances is somewhat arbitrary, as emerging evidence reveals new immunomodulatory roles for these therapies. Finally, these therapeutic advances suggest a change in the treatment approach for less common liver cancers, such as sarcomatoid HCC and combined HCC-cholangiocarcinoma. Recent clinical experiences and genomic data indicate potential responsiveness to immune checkpoint inhibitors. Including these subtypes in clinical trials may help accelerate the development of effective treatments for these uncommon entities.enBile duct cancerCellular therapyCholangiocarcinomaImmunotherapyLiver neoplasmPersonalized therapyTargeted agentsreview10.1016/j.jhep.2025.08.01840865646