Editorial: Immune Checkpoint Inhibitors in Hepatocellular Carcinoma Prior to Liver Transplantation—Current Evidence and Future Directions

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of hepatocellular carcinoma (HCC). More recently, accumulating evidence suggests that ICIs can be safely and effectively used as downstaging or bridging therapy prior to liver transplantation (LT) [1-4]. However, most available data are derived from small retrospective studies lacking appropriate control groups (e.g., patients who did not receive ICIs before LT), limiting the ability to draw firm conclusions or make evidence-based recommendations. In this multicenter retrospective propensity score–matched study, Aceituno et al. compared ICI-treated patients (bridging, downstaging, or palliative; n = 48) with non-ICI controls (n = 144) who underwent LT [5]. Over a median follow-up of 36.5 (21.0–50.0) months, there were no significant differences in allograft rejection (18.8% vs. 19.4%, p = 0.916) or graft failure (4.2% vs. 2.1%, p = 0.6) between the two groups, consistent with prior reports (Table 1). All rejection episodes were successfully treated, with no rejection-related deaths; one ICI-treated patient required re-transplantation. Notably, 16.7% of ICI-treated patients received ATG induction, all without rejection or recurrence. Although center-specific immunosuppression protocols were not matched, ATG induction may represent a strategy to balance immunosuppression in high-risk patients and warrants further study. Rejection did not affect overall survival, though larger studies with longer follow-up are needed to assess the impact of rejection on overall survival (OS), taking into consideration rejection severity. Of note, they reported differences in ICI-related variables by rejection status. Washout interval was significantly different between rejection and non-rejection cases, and > 50% of rejection cases had an ICI washout ≤ 50 days. The authors reported that 66.7% of rejection cases had ICI exposure ≥ 1 year versus 25.6% in non-rejection cases. Also, patients with ICI exposure < 90 days had higher HCC recurrence (37.5% vs. 5%, p = 0.027), suggesting that ICI exposure of ≥ 3 but < 12 months may reduce both rejection and recurrence risk, which requires further validation in a future larger prospective study. Despite matching for rejection-related factors, important differences remained (macrovascular invasion in 18.8% of ICI cases vs. none in non-ICI; ICI group had ~two-thirds beyond Milan criteria vs. ~one-third in non-ICI groups; ~20% of ICI cases did not receive locoregional therapies while nearly all non-ICI did). Despite these differences, no significant differences were reported for HCC recurrence (p = 1) or OS (p = 0.62), and HCC-related deaths were fewer in the ICI group (n = 2 vs. 8). The small number of cases and resulting limited statistical power, along with the exclusion of waitlist dropouts, preclude an intention-to-treat interpretation of outcomes. Therefore, beyond rejection, long-term pre- and post–liver transplantation outcomes must be carefully evaluated in future prospective multicenter studies. In conclusion, this multicenter propensity score–matched study advances the field by demonstrating the safety of immune checkpoint inhibitor therapy prior to liver transplantation compared with no ICI exposure. However, important questions remain regarding optimal ICI characteristics, patient selection, use in macrovascular invasion, validation of recurrence risk scores, prognostic value of complete pathological response, integration with locoregional or systemic therapies, and optimal post-transplant immunosuppression, which should be addressed in future studies [10]. Mohammad Saeid Rezaee-Zavareh: conceptualization, methodology, writing – original draft. Ju Dong Yang: writing – review and editing, writing – original draft, conceptualization, methodology. Dr. Ju Dong Yang: research supported by National Cancer Institute (NCI) R21CA280444. Dr. Ju Dong Yang reports the following conflicts of interest: consulting service for AstraZeneca, Eisai, Exact Sciences, and Fujifilm Medical Sciences. Mohammad Saeid Rezaee-Zavareh declares no conflicts of interest. This article is linked to Aceituno et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70528 and https://doi.org/10.1111/apt.70590. The authors have nothing to report.