Immunotherapy and transplantation for hepatocellular carcinoma

Immune checkpoint inhibitors (ICIs) have emerged as the primary treatment for advanced hepatocellular carcinoma (HCC) and have shown promise in the neoadjuvant setting prior to resection. Liver transplantation (LT) is the preferred treatment for unresectable early HCC or locally advanced disease post locoregional therapy, but the need for immunosuppression after LT conflicts with ICIs' immune augmenting effects. Neoadjuvant ICI may benefit select LT candidates, but challenges arise in understanding response indicators and managing post-LT risks. Reports of severe rejection after LT have raised concerns, though liver-specific factors may mitigate rejection risks, prompting exploration of pre-LT ICI usage. While focus has been on PD-1/PD-L1 inhibitors, the optimal pre-LT ICI regimen remains uncertain, and trials must emphasize careful patient selection and management. Living donor LT is advantageous because ICIs can be withheld for a predefined washout period. In the post-LT setting, use of ICIs is generally avoided, though a few reports suggest that PD-L1 expression in the transplanted liver may be a safety biomarker and that, despite the risk, ICI therapy may be better than supportive care for patients with otherwise-untreatable HCC recurrence. This expert opinion highlights the complexities in the management of HCC vis-à-vis LT. Prospective studies and biomarkers are needed to define safe and effective pre- and post-LT immunotherapy protocols.