Beyond rejection risk: Identifying ideal candidates for pretransplant immune checkpoint inhibitors for HCC

The role of immune checkpoint inhibitors (ICIs) before liver transplantation (LT) for HCC remains uncertain. In particular, the optimal treatment duration and the potential long-term oncologic benefits remain unclear. Thus, we conducted a systematic review to evaluate outcomes of ICI as bridging or downstaging therapy before LT. Following PRISMA guidelines (PROSPERO CRD1082620), 5 databases were systematically searched up to March 2025. All published studies reporting ICI before LT in HCC were included. Data were synthesized descriptively, and exploratory regression models, including restricted cubic splines, were performed. Thirty-nine studies comprising 261 patients were included. Most were male (87.3%), over 50 years old, and had viral hepatitis as the predominant etiology of their liver disease. ICIs were mainly used for downstaging (84.2%), most frequently using nivolumab (24.5%). The median ICI duration was 63 days (42-105), with a median washout period of 57 days (29-116). Most patients presented with multifocal disease (77.9%) and tumors beyond Milan criteria, with a median largest lesion size of 37.5 mm (9.4-78.5). Macrovascular invasion was present in 15.7%. Posttransplant recurrence occurred in 18.6%. Shorter ICI exposure was significantly associated with a higher risk of recurrence (OR: 0.9; p <0.001). Spline models demonstrated that the benefit of ICI treatment was achieved at 80 days. Paradoxically, patients with BCLC A exhibited higher recurrence risk (OR: 5.2; p =0.01), perhaps underscoring the limitations of conventional staging in candidate selection. Allograft rejection occurred in 23.0% of patients and led to graft failure in 14.7%. Younger age (<50 y) and a shorter washout period (<50 d) were independently associated with an increased risk of recurrence and rejection, respectively. The duration of ICI treatment before LT is a critical factor influencing HCC recurrence risk, with an optimal treatment duration of more than 80 days. Furthermore, a confirmatory washout period of at least 50 days appears to be important to mitigate the risk of rejection.