ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy

In this study, Wang et al. show that the inhibition of ATR kinase affords selective lethality to mismatch repair-deficient (MMR-d) cancer cells by promoting MUS81 nuclease- and replication-dependent DNA damage, increasing cytosolic DNA fragments, and activating cGAS signaling. The consequent interferon response potentially stimulates cytotoxic T-cell-dependent antitumor immunity and points to ATR inhibition as a notable strategy to augment PD-1 targeting immunotherapies against MMR-d cancers.