ADAR and neoplasm: In this work, we uncover a robust and penetrant synthetic lethality (SL)16 between BRCA1/2 and ADAR1. In contrast to other BRCA1/2 SL effects – such as that mediated by PARP inhibitors which relies on DNA damage, cGAS-STING pathway activation and T-cell-mediated adaptive immune response17,18, we show that the BRCA1/2–ADAR1 SL is a tumor cell-autonomous effect not only caused by R-loops, but importantly, by a resultant PRR activation leading to autocrine interferon poisoning.