Liver Transplantation Following Immune Checkpoint Inhibitor Therapy: What Do We Need to Know from Clinical and Immunological Perspective?

Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of advanced hepatocellular carcinoma (HCC), establishing immunotherapy-based combinations as the standard of care. Improved treatment responses have expanded liver transplant eligibility for selected patients with advanced HCC through downstaging or bridging strategies. Such advances have directly influenced transplant candidacy and post-transplant outcomes. However, accumulating evidence indicates that pretransplant exposure to ICIs may disrupt post-transplant immune homeostasis, increasing the risk of acute allograft rejection and graft failure requiring retransplantation. From an immunological perspective, rejection following pretransplant ICI therapy predominantly manifests as T cell-mediated rejection and is characterized by the sustained activation of effector T cells and impairment of regulatory immune pathways. Blockade of immune checkpoint signaling interferes with mechanisms critical for allograft tolerance, including T cell apoptosis and regulatory T cell induction. Recent studies further underscore the importance of the washout period between ICI discontinuation and LT, with longer washout intervals being associated with lower rejection rates. Importantly, timely recognition and appropriate immunosuppressive management can often resolve acute rejection without adversely affecting long-term graft outcomes. This review integrates current immunological insights with emerging clinical evidence to inform optimal transplant timing and management strategies for liver transplant candidates receiving ICIs.