随着免疫检查点抑制剂（ICI）获得批准，晚期肝细胞癌（HCC）的系统治疗在过去几年中发生了革命性的变化。尽管 ICI 联合治疗方案有望延长生存期，但反应并未普遍出现，程序性细胞死亡 1 通路抑制剂的最佳搭档仍有待确定。用于单一疗法的 ICI 所取得的令人鼓舞的结果甚至更少。迄今为止，已经描述了几种耐药机制，涉及癌细胞的特征（内在机制）和周围肿瘤微环境（外在机制）。与治疗相关的因素也可能导致耐药性的产生。越来越多的研究工作致力于发现克服耐药性的新方法和靶点，其中一些可能在未来引入临床。在此，我们描述了一系列参与损害 ICI 反应的耐药机制，并提出了克服耐药性的潜在治疗方法。© 2023 Manfredi 等人。

Systemic treatment for advanced hepatocellular carcinoma (HCC) has been revolutionized over the last few years following the approval of immune checkpoint inhibitors (ICI). Despite the promising survival extension seen with ICI combination regimens, responses are not universally seen and the optimal partner for programmed cell death 1 pathway inhibitors remains to be identified. Even fewer encouraging results have been demonstrated with ICI used for monotherapy. Several mechanisms of resistance have been described so far, involving characteristics of cancer cells (intrinsic mechanisms) and of the surrounding tumor microenvironment (extrinsic mechanisms). Factors related to therapy may also contribute to the development of resistance. Increasing research efforts are being dedicated to the discovery of novel approaches and targets to overcome resistance, some of which may be introduced into clinic in the future. Herein we describe a selection of resistance mechanisms that have been involved in impairing response to ICI and propose potential therapeutic approaches to overcome resistance.© 2023 Manfredi et al.