Peri-transplant use of immune checkpoint inhibitors in hepatocellular carcinoma: a transplant oncology perspective on safety, timing, post-transplant management, and future directions.

Immune checkpoint inhibitors (ICPIs) targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) pathways have transformed systemic therapy for advanced hepatocellular carcinoma (HCC), prompting exploration of their neoadjuvant role in downstaging tumors to meet the liver transplantation (LT) criteria. While ICPIs have demonstrated impressive tumor responses and survival benefits in non-transplant settings, their peri-transplant application is limited by the substantial risk of acute graft rejection due to immune activation against the allograft. Retrospective data indicate rejection rates of approximately 18%-26% pre-LT and 28%-37% post-LT, with fatal outcomes in a subset of cases. Optimal washout periods (typically ≥50-90 days, ideally ~3 months), PD-L1 graft expression, and intensified immunosuppression appear to mitigate but not eliminate the risk. Living donor LT offers scheduling advantages for precise timing. Post-transplant ICPI use remains high-risk and requires individualized decision-making. Emerging biomarkers (e.g., graft PD-L1, ctDNA, and tumor mutational burden) and surveillance strategies hold promise for risk stratification. This review examines the safety profile, timing considerations, class-specific differences, post-LT palliative applications, and innovations needed for the safe incorporation of ICPIs into the transplant oncology protocols for HCC.