Abstract
Genomic instability is a defining feature of cancer that fuels transformation, tumor evolution, and therapeutic resistance. However, genomic instability also incurs an immunological liability by generating cytosolic DNA, a potent trigger of cGAS-STING signaling. In this review, we summarize recent advances in our understanding of the sources of immunostimulatory cytosolic DNA in genomically unstable cancer cells. We examine how newly identified regulatory mechanisms, including chromatin-mediated cGAS suppression, influence the immune-activating potential of cytosolic DNA generated by genomic instability. We also highlight how key regulators, such as the exonuclease TREX1, may be co-opted to shield genomically unstable cancer cells from immune surveillance. By synthesizing these recent advances in our understanding of cGAS-STING activation and regulation in cancer, we aim to highlight emerging therapeutic strategies that leverage cGAS signaling to bolster antitumor immunity.