癌细胞的错配修复（MMR）缺陷会驱动突变，并为免疫治疗提供有用的生物标志物。然而，许多 MMR 缺陷 (MMR-d) 肿瘤对免疫疗法没有反应，这突出表明需要寻找针对 MMR-d 癌细胞的替代方法。在这里，我们发现抑制 ATR 激酶会优先杀死 MMR-d 癌细胞。从机制上讲，ATR 抑制剂 (ATRi) 通过以复制和 MUS81 核酸酶依赖性方式诱导 DNA 损伤，对 MMR-d 细胞施加合成致死作用。 ATRi 诱导的 DNA 损伤与 MSH2 和 PCNA 共定位，表明它是由复制过程中 MMR 蛋白识别的 DNA 结构引起的。在同基因小鼠模型中，ATRi 有效减少 MMR-d 肿瘤的生长。有趣的是，ATRi 的抗肿瘤作用部分归功于 CD8 T 细胞。在 MMR-d 细胞中，ATRi 刺激细胞质中新生 DNA 片段的积累，激活 cGAS 介导的干扰素反应。 ATRi 和抗 PD-1 抗体的组合比单独使用 ATRi 或抗 PD-1 抗体更有效地减少 MMR-d 肿瘤的生长，显示了 ATRi 增强 MMR-d 肿瘤免疫治疗的能力。因此，ATRi 通过诱导合成致死性和增强抗肿瘤免疫选择性地靶向 MMR-d 肿瘤细胞，为补充和增强 MMR 缺陷引导的免疫治疗提供了一种有前途的策略。© 2023 Wang 等人；由冷泉港实验室出版社出版。

The mismatch repair (MMR) deficiency of cancer cells drives mutagenesis and offers a useful biomarker for immunotherapy. However, many MMR-deficient (MMR-d) tumors do not respond to immunotherapy, highlighting the need for alternative approaches to target MMR-d cancer cells. Here, we show that inhibition of the ATR kinase preferentially kills MMR-d cancer cells. Mechanistically, ATR inhibitor (ATRi) imposes synthetic lethality on MMR-d cells by inducing DNA damage in a replication- and MUS81 nuclease-dependent manner. The DNA damage induced by ATRi is colocalized with both MSH2 and PCNA, suggesting that it arises from DNA structures recognized by MMR proteins during replication. In syngeneic mouse models, ATRi effectively reduces the growth of MMR-d tumors. Interestingly, the antitumor effects of ATRi are partially due to CD8+ T cells. In MMR-d cells, ATRi stimulates the accumulation of nascent DNA fragments in the cytoplasm, activating the cGAS-mediated interferon response. The combination of ATRi and anti-PD-1 antibody reduces the growth of MMR-d tumors more efficiently than ATRi or anti-PD-1 alone, showing the ability of ATRi to augment the immunotherapy of MMR-d tumors. Thus, ATRi selectively targets MMR-d tumor cells by inducing synthetic lethality and enhancing antitumor immunity, providing a promising strategy to complement and augment MMR deficiency-guided immunotherapy.© 2023 Wang et al.; Published by Cold Spring Harbor Laboratory Press.