TREX1, but not other DEDDh exonucleases, restrains cGAS-STING activation by cytosolic DNA. Zhu et al. examine the basis for this specificity and define a modular double-stranded DNA (dsDNA)-recognition architecture within TREX1 comprising R128, a substrate-sensing loop, and an auxiliary DNA-binding surface, linking dsDNA recognition to immune control and antitumor immunity.
