Shrinking Giants: On the Feasibility of Downsizing Hepatocellular Carcinoma with Immunotherapy Prior to Liver Transplantation

Background/Objectives: Hepatocellular carcinoma (HCC) is a major cause of cancer-related morbidity and mortality, with incidence expected to increase. Liver transplantation is the most definitive curative option for early HCC, but many patients present beyond accepted transplant criteria, including the Milan criteria. Downstaging aims to reduce tumor burden and enable transplantation without compromising long-term outcomes. Methods: We reviewed the literature on liver transplantation, immune checkpoint inhibitors, immunotherapy–locoregional therapy combinations, and immune-related adverse events in HCC. Results: Immunotherapy-based strategies are emerging as downstaging approaches in selected patients. In advanced HCC, immune checkpoint inhibitor combinations have improved objective response rates compared with tyrosine kinase inhibitors, reaching approximately 20–36% in pivotal phase III trials. In the downstaging setting, early data suggest that immune checkpoint inhibitors, particularly with locoregional therapies, can achieve sufficient tumor regression to permit transplantation in patients initially beyond criteria. The ImmunoXXL trial reported successful downstaging and transplantation in all 16 patients treated with atezolizumab–bevacizumab, with 62.5% complete pathological responses, 2-year recurrence-free survival of 90%, and overall survival of 94%. The VITALITY study achieved successful downstaging in 75.6% of patients beyond Milan criteria, with 36.7% undergoing transplantation and 3-year post-transplant survival of 85%. However, pre-transplant immune checkpoint inhibitor exposure carries a clinically relevant risk of acute allograft rejection, reported in approximately 16–28% of transplanted patients. Conclusions: Immunotherapy-based downstaging before liver transplantation is promising but remains non-standard. Its use should be restricted to carefully selected patients within multidisciplinary protocols, as evidence remains limited by small cohorts, heterogeneous regimens, uncertain washout intervals, and rejection risk.