Qihuang Jin

Highlights • dMLH1 tumor cells accumulate cytosolic DNA and produce IFN-β • Knockout of cGAS or STING in dMLH tumor cells renders resistance to checkpoint blockade • Downregulating cGAS-STING in human dMLH1 cancers impairs checkpoint blockade therapy Summary Increased neoantigens in hypermutated cancers with DNA mismatch repair deficiency (dMMR) are proposed as the major contributor to the high objective response rate in anti-PD-1 therapy.

Highlights • MLH1 deficiency triggers cytosolic DNA release and activates the cGAS-STING pathway • MLH1 regulates Exo1 nuclease activity during DNA end resection • Loss of MLH1 leads to DNA hyperexcision, RPA exhaustion, and chromosomal instability Summary Tumors with defective mismatch repair (dMMR) are responsive to immunotherapy because of dMMR-induced neoantigens and activation of the cGAS-STING pathway.