Epigenetic mechanisms in HCC immune landscape: Therapeutic implications

Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor and is currently a major cause of cancer-related mortality worldwide. The arrival of immune checkpoint inhibitors (ICI), and their combination with anti-VEGF/VEGFR antibodies, has transformed the treatment of patients with advanced HCC. Still, only about 30 % of patients respond to therapy, and these cases are among those displaying an immune-enriched ("immune-hot") tumor microenvironment (TME). Therefore, the identification of combination strategies that can overcome ICI resistance is of high relevance. Epigenetic alterations are increasingly recognized to impact on tumor development, contributing to practically all the hallmarks of cancer. These mechanisms not only promote the growth and survival of cancer cells, also determine the phenotype of immune cells and other components of the TME, driving tumor progression and resistance to therapies. Emerging preclinical evidence in different tumor types indicates that the combination with the so-called epi-drugs can increase the efficacy and overcome resistance to ICI. Here, we provide an overview of the epigenetic rewiring occurring in cancer and immune cells that can hinder antitumor immunity and ICI's efficacy in HCC. We also discuss how epigenetically targeted therapies may be leveraged to synergize with ICI and potentially treat immune-cold HCCs.