Beyond apoptosis: the emerging landscape of non-canonical cell death in hepatobiliary malignancies and immunotherapeutic strategies

Abstract

Non-apoptotic cell death modalities shape the tumor immune microenvironment and treatment outcomes in hepatobiliary cancers. Ferroptosis could directly kill cancer cells and enhance antitumor immunity and immunotherapy efficacy, but it may also promote immunosuppression in some contexts. Cuproptosis could eliminate tumor cells, activate antitumor immune responses, and sensitize tumors to immunotherapy. Pyroptosis could induce immunogenic cell death, amplify antitumor immunity, and synergize with immune checkpoint inhibitors. Necroptosis may foster an immunologically active microenvironment and has therapeutic potential, although its clinical relevance requires further study. Disulfidptosis was a newly recognized vulnerability that may elicit antitumor immune responses. Simultaneous engagement of multiple cell death pathways may cooperatively reshape the tumor microenvironment and help overcome therapeutic resistance. Combining two or more cell death modalities may therefore kill hepatobiliary cancer cells directly while establishing an antitumor immune microenvironment.