Tumors with defective mismatch repair (dMMR) are responsive to immunotherapy because of dMMR-induced neoantigens and activation of the cGAS-STING pathway. While neoantigens result from the hypermutable nature of dMMR, it is unknown how dMMR activates the cGAS-STING pathway. We show here that loss of the MutLα subunit MLH1, whose defect is responsible for ~50% of dMMR cancers, results in loss of MutLα-specific regulation of exonuclease 1 (Exo1) during DNA repair. This leads to unrestrained DNA excision by Exo1, which causes increased single-strand DNA formation, RPA exhaustion, DNA breaks, and aberrant DNA repair intermediates. Ultimately, this generates chromosomal abnormalities and the release of nuclear DNA into the cytoplasm, activating the cGAS-STING pathway. In this study, we discovered a hitherto unknown MMR mechanism that modulates genome stability and has implications for cancer therapy.

由于 dMMR 诱导的新抗原和 cGAS-STING 通路的激活，具有缺陷错配修复 (dMMR) 的肿瘤对免疫治疗有反应。虽然新抗原是由 dMMR 的超可变性质产生的，但尚不清楚 dMMR 如何激活 cGAS-STING 通路。我们在此表明​​，MutLα 亚基 MLH1 的缺失导致约 50% 的 dMMR 癌症的缺陷导致 DNA 修复过程中外切核酸酶 1 (Exo1) 的 MutLα 特异性调节缺失。这导致 Exo1 无限制地切除 DNA，从而导致单链 DNA 形成增加、RPA 耗尽、DNA 断裂和异常 DNA 修复中间体。最终，这会产生染色体异常并将核 DNA 释放到细胞质中，从而激活 cGAS-STING 通路。在这项研究中，