Immune checkpoint inhibitor resistance in hepatocellular carcinoma

The application of immune checkpoint inhibitors (ICIs) has markedly enhanced the treatment of hepatocellular carcinoma (HCC), and HCC patients who respond to ICIs have shown prolonged survival. However, only a subset of HCC patients benefit from ICIs, and those who initially respond to ICIs may develop resistance. ICI resistance is likely related to various factors, including the immunosuppressive tumor microenvironment (TME), the absence of antigen expression and impaired antigen presentation, tumor heterogeneity, and gut microbiota. Therefore, exploring the possible mechanisms of ICI resistance is crucial to improve the clinical benefit of ICIs further. Various combination therapies for HCC immunotherapy have prevented and reversed ICI resistance to a certain extent. In addition, many new combination therapies that can overcome resistance are being explored. This review seeks to characterize the complex TME in HCC, explore the possible mechanisms of immune resistance to ICIs in different resistance categories, and review the combination therapies currently being applied and those under investigation for immunotherapy.