Advancing Adjuvant Immunotherapy in Hepatocellular Carcinoma: A Comprehensive Review.

Abstract

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally, with high rates of recurrence even after curative-intent treatments such as hepatectomy and liver transplantation (LT). In recent years, immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape for HCC, demonstrating significant efficacy among advanced-stage tumors through combination regimens, such as anti-programmed cell death ligand-1 (PD-L1)/PD-1 inhibitors with anti-vascular endothelial growth factor agents. Recent advances have highlighted the potential of ICIs as adjuvant therapy to improve recurrence-free survival among high-risk patients post-resection. However, challenges such as low immunogenicity, the immunosuppressive tumor microenvironment, and immune resistance remain substantial barriers to the broader success of ICIs. In the context of LT, the use of ICIs is further complicated by the concurrent need for immunosuppressive agents, which can exacerbate the risk of recurrence. Emerging strategies focusing on the optimization of the timing of ICI therapy and the utilization of novel biomarkers are being explored to mitigate graft rejection while maintaining antitumor efficacy. Additionally, immune-cell-based therapies based on chimeric antigen receptor-T and natural killer (NK) cells, adoptive cell transfer, and liver-resident NK cell approaches are also being investigated for their potential to reduce recurrence and improve survival outcomes. This review focuses on the current landscape of adjuvant immunotherapy and immune-cell therapy in the postoperative management of HCC, highlighting ongoing clinical trials, therapeutic potential, and associated risks. With continued advancements in immunotherapeutic strategies and personalized approaches, these therapies hold the promise of transforming outcomes for patients undergoing curative resection or LT.