The immunological paradox: immune checkpoint inhibitors in liver transplantation

The incorporation of immune checkpoint inhibitors (ICIs) into the treatment repertoire for hepatocellular carcinoma (HCC) and advanced biliary tract cancers has significantly transformed the field of oncology, offering remarkable survival advantages. However, the interaction of these powerful immunomodulators with liver transplantation (LT), the ultimate curative intervention for end-stage liver disease, presents a complex immunological paradox. While LT depends on the induction and maintenance of immune tolerance to suppress alloimmune responses and prevent allograft rejection, ICIs operate by disrupting these tolerance mechanisms to enhance host antitumor immunity. This comprehensive review synthesizes the latest evidence from 2024 and 2025, incorporating key findings from the VITALITY study, international washout cohorts, and meta-analyses of individual patient data. The historical "Liver Tolerance Effect," the mechanistic role of the PD-1/PD-L1 axis as a crucial protector of hepatic integrity, and the severe phenomenon of ICI-induced fatal hepatic necrosis are critically examined in this review. Furthermore, the emerging utility of precision predictive biomarkers, including immune-related adverse events (irAEs), the Eplet Risk Score, and intragraft PD-L1 expression as tissue-based predictors of post-transplant ICI-induced rejection, was rigorously analyzed to stratify rejection risk. By examining the pharmacodynamic conflict between systemic tumor eradication and localized graft preservation, this report provides a pragmatic, evidence-based framework for candidate selection, optimal washout timing, and post-transplant management, ultimately culminating in a critical appraisal of the ethical imperatives surrounding living donor liver transplantation.