The advent of immune checkpoint blockers (ICB) has revolutionized patient outcome in many tumor types. However, only a minority of patients truly benefits from these therapies and displays a durable and robust anti-tumor response that translates into improved outcome. Thorough mechanistic preclinical studies and comprehensive investigations performed in tumor biopsies of patients treated with ICB have unveiled multiple resistance mechanisms involving both tumor-intrinsic and tumor-extrinsic characteristics. Here, we comprehensively review all known tumor-intrinsic genetic and epigenetic resistance mechanisms to ICB, provide an evaluation of their current level of evidence and propose rationale therapeutic strategies to circumvent them.

免疫检查点阻滞剂（ICB）的出现彻底改变了许多肿瘤类型的患者预后。但是，只有少数患者真正受益于这些疗法，并且显示出持久而强大的抗肿瘤反应，可以转化为更好的结果。在对接受ICB治疗的患者的肿瘤活检中进行的彻底的机械前临床研究和综合研究，揭示了涉及肿瘤内在和肿瘤外在特征的多种耐药机制。在这里，我们全面回顾了所有已知的对ICB的肿瘤内在遗传和表观遗传抗性机制，提供了对它们当前证据水平的评估，并提出了合理的治疗策略来规避它们。