肝细胞癌（HCC）是全球癌症相关死亡的第二大原因。不能手术的HCC患者的五年生存率约为12％。肝肿瘤微环境（TME）具有免疫耐受性，并且严重浸润着免疫抑制细胞。在某些情况下，免疫检查点抑制剂（ICIs）可以逆转肿瘤细胞免疫逃逸并增强抗肿瘤免疫力。快速发展的ICIs已扩展了晚期HCC的系统治疗选择;然而，单一药物ICIs在晚期HCC中只能实现有限的15-20％客观反应率。因此，其他组合方法可以增强ICIs的疗效或抑制其他促进肿瘤的途径，从而增强临床疗效。表观遗传变化（例如染色质状态和非基因DNA修饰的改变）已被证明推动HCC肿瘤生长和进展以及它们对ICIs的反应。最近的研究在临床前和临床设置中将ICIs和表观遗传学抑制剂结合起来，以控制几种癌症，包括HCC。在本综述中，我们概述了HCC的当前ICI治疗方法，它们成功和失败的机制，以及如何将ICIs与不同的表观遗传学抑制剂相结合，以增加ICIs的持久性，潜在地治疗“免疫冷”HCC。©2023.作者（s），在Springer Nature Limited的独家许可下。

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. The five-year survival rate of patients with unresectable HCC is about 12%. The liver tumor microenvironment (TME) is immune tolerant and heavily infiltrated with immunosuppressive cells. Immune checkpoint inhibitors (ICIs), in some cases, can reverse tumor cell immune evasion and enhance antitumor immunity. Rapidly evolving ICIs have expanded systemic treatment options in advanced HCC; however, single-agent ICIs achieve a limited 15-20% objective response rate in advanced HCC. Therefore, other combinatorial approaches that amplify the efficacy of ICIs or suppress other tumor-promoting pathways may enhance clinical outcomes. Epigenetic alterations (e.g., changes in chromatin states and non-genetic DNA modifications) have been shown to drive HCC tumor growth and progression as well as their response to ICIs. Recent studies have combined ICIs and epigenetic inhibitors in preclinical and clinical settings to contain several cancers, including HCC. In this review, we outline current ICI treatments for HCC, the mechanism behind their successes and failures, and how ICIs can be combined with distinct epigenetic inhibitors to increase the durability of ICIs and potentially treat "immune-cold" HCC.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.