The DNA mismatch repair pathway is involved in the identification, excision, and repair of base-base mismatches and indel loops in the genome. Mismatch repair deficiency occurs in approximately 20% of all cancers and results in a type of DNA damage called microsatellite instability. In 2017, the immune checkpoint inhibitor, Pembrolizumab, an anti-PD-1 therapy, was approved for use in all unresectable or metastatic tumours that were mismatch repair deficient or had high microsatellite instability regardless of tissue origin. This landmark approval was the first time a drug had been approved in a site agnostic way, but accumulating data has revealed that up to 50% of mismatch repair deficient tumours are refractory to treatment and there is a huge amount of variability in the therapeutic benefit amongst responders. Several mechanisms of resistance to immune checkpoint blockade for mismatch repair deficient cancers have been identified but our understanding of what is driving resistance in a proportion of patients remains lacking. In this review article, we discuss the emerging mechanisms of resistance which may enable optimal stratification of patients for treatment with immune checkpoint inhibitors in the future.

DNA错配修复途径涉及基因组中碱基错配和插入缺失环的识别、切除和修复。大约 20% 的癌症发生错配修复缺陷，并导致一种称为微卫星不稳定性的 DNA 损伤。2017年，免疫检查点抑制剂Pembrolizumab（一种抗PD-1疗法）被批准用于所有错配修复缺陷或具有高度微卫星不稳定性的不可切除或转移性肿瘤，无论组织来源如何。这一具有里程碑意义的批准是药物首次以与位点无关的方式获得批准，但积累的数据显示，高达 50% 的错配修复缺陷肿瘤难以治疗，并且不同人群的治疗效果存在巨大差异。响应者。已经确定了针对错配修复缺陷癌症的免疫检查点阻断的几种抵抗机制，但我们仍然缺乏对部分患者抵抗力驱动因素的了解。在这篇综述文章中，我们讨论了新出现的耐药机制，这可能有助于未来对接受免疫检查点抑制剂治疗的患者进行最佳分层。