DNA double-strand break (DSB) repair inhibitors are known to enhance therapeutic efficacy of DNA damage-inducing agents, but molecular mechanisms underlying this enhancement have not been fully solved. In their study on page 568, Carr and colleagues demonstrate that DNA DSB repair inhibitor peposertib augments cell death and inflammation in response to radiation-induced DNA damage. Depicted on the cover is an immunofluorescent image of lung cancer cells after treatment with radiation and peposertib. The p53-null senescent-like cells fluoresce green due to α-tubulin staining, with DAPI-stained nuclei fluorescing blue. Treatment-induced DNA damage is visible as pink puncta owing to γH2Ax staining. The authors found that p53-deficient cancer cells progress through the cell cycle despite therapy-induced DNA damage, and that cGAS detects cytosolic DNA in micronuclei and induces inflammatory signaling and programmed cell death ligand 1 (PD-L1) expression in those cells. Accordingly, PD-L1 blockade enhances efficacy of combination radiation-peposertib treatment in vivo. This article is also Highlighted on page 499.