The study investigates the role of cGAS (cyclic GMP-AMP synthase) in the surveillance of micronuclei, which are structures formed due to genome instability. cGAS is a cytosolic sensor of double-stranded DNA (dsDNA) and its activation is implicated in autoinflammatory disorders and DNA damage. The research shows that cGAS localizes to micronuclei, both in response to exogenous DNA damage and spontaneously in human cancer cells. Micronuclei form during mitosis when DNA mis-segregates, and they are surrounded by their own nuclear membrane. The breakdown of this membrane, a process associated with chromothripsis, exposes the chromatin within the micronucleus to the cytoplasm, leading to cGAS accumulation and activation. cGAS binds to and is activated by chromatin, and the formation of micronuclei and the proinflammatory response following DNA damage are cell-cycle dependent. Using live-cell laser microdissection and single-cell transcriptomics, the study demonstrates that interferon-stimulated gene (ISG) expression is induced in micronucleated cells. This suggests that micronuclei serve as a significant source of immunostimulatory DNA, and that cGAS recognition of micronuclei may act as an intrinsic immune surveillance mechanism detecting a range of neoplasia-inducing processes. The findings highlight the importance of micronuclei in linking genome instability to innate immune responses, with potential implications for both cancer and autoinflammation.The study investigates the role of cGAS (cyclic GMP-AMP synthase) in the surveillance of micronuclei, which are structures formed due to genome instability. cGAS is a cytosolic sensor of double-stranded DNA (dsDNA) and its activation is implicated in autoinflammatory disorders and DNA damage. The research shows that cGAS localizes to micronuclei, both in response to exogenous DNA damage and spontaneously in human cancer cells. Micronuclei form during mitosis when DNA mis-segregates, and they are surrounded by their own nuclear membrane. The breakdown of this membrane, a process associated with chromothripsis, exposes the chromatin within the micronucleus to the cytoplasm, leading to cGAS accumulation and activation. cGAS binds to and is activated by chromatin, and the formation of micronuclei and the proinflammatory response following DNA damage are cell-cycle dependent. Using live-cell laser microdissection and single-cell transcriptomics, the study demonstrates that interferon-stimulated gene (ISG) expression is induced in micronucleated cells. This suggests that micronuclei serve as a significant source of immunostimulatory DNA, and that cGAS recognition of micronuclei may act as an intrinsic immune surveillance mechanism detecting a range of neoplasia-inducing processes. The findings highlight the importance of micronuclei in linking genome instability to innate immune responses, with potential implications for both cancer and autoinflammation.