The role of immunotherapy prior to liver transplantation in advanced or down-staged HCC – timing of transplants, selection of patients, and hurdles to overcome with immunosuppression

Immune checkpoint inhibitors (ICIs) have revolutionized the management of hepatocellular carcinoma (HCC). Landmark trials, including IMbrave150 and HIMALAYA, have established combination ICI therapies as the standard of care for advanced HCC. Beyond these indications, ICIs are now being explored as neoadjuvant therapies for liver transplantation (LT), offering potential benefits in downstaging tumors and serving as bridging therapies for patients outside traditional transplant eligibility criteria. While early evidence from case reports and trials highlights promising oncologic and survival outcomes, the current understanding of ICI use before LT introduces new, unexplored challenges. Allograft rejection, safety concerns regarding immune-related adverse events, and the effective management of the complex interplay between immunosuppression and immune therapy represent ongoing themes of discussion. The tumor microenvironment and immunomolecular profiles, which critically influence ICI efficacy, remain the true cornerstones of patient stratification that are yet to be fully understood. Additionally, the lack of reliable biomarkers and the limitations of current radiologic criteria complicate treatment planning and response evaluation. Overcoming these obstacles requires multidisciplinary collaboration, refined patient selection strategies, and robust clinical trials to establish the safety and efficacy of ICIs in this context. This review aims to provide an up-to-date summary of the ever-evolving role of ICIs in LT strategies, offering a comprehensive overview of proposed therapeutic protocols, their oncologic and safety profiles, and the integration of emerging biological insights into clinical practice.