The life of any organism depends on the ability of cells to accurately recognize and eliminate harmful microbes. To detect the immense repertoire of pathogenic entities, the mammalian innate immune system has evolved distinct sensing strategies, including a central one based on the recognition of DNA—the basic building block of “life” itself. Integral to this process is the intracellular enzyme cGAS, which upon binding to double-stranded DNA (dsDNA), initiates a tightly regulated signaling cascade involving the adapter STING to trigger a variety of inflammatory effector responses. Although this process was originally discovered as a crucial component of innate immune defense against pathogens, recent work has elucidated a role for cytosolic DNA recognition pathways beyond the “classical” realm of innate immunity. The realization of an important involvement of cGAS and STING in various biological contexts has broadened its implications for human health and disease—much more than initially anticipated.

Early structural and functional studies on cyclic guanosine monophosphate–adenosine monophosphate (GMP–AMP) synthase (cGAS) have established its capability to interact with dsDNA in a sequence-independent manner. Although this indiscriminate sensing strategy ensures the detection of almost all pathogenic entities, it also enables immune responses to be elicited upon encountering self-DNA. Mechanistically, self-DNA–sensing phenomena can be provoked by diverse alterations of both the extracellular and intracellular milieu, such as perturbations of DNA compartmentalization or disturbances in endogenous DNA metabolism. Initial studies on the relevance of cGAS-dependent recognition of self-DNA have largely focused on bona fide immunological consequences, such as inherited autoimmune and autoinflammatory disorders. Indeed, mutations in genes affecting intracellular DNA turnover can cause rare monogenic autoinflammatory syndromes in which the aberrant stimulation of innate DNA sensing is unequivocally central in driving associated pathologies. In addition to these rather traditional immunological disease entities, the aberrant activation of innate DNA sensing has recently emerged as an underlying cause for a number of distinct biological phenomena. Studies have documented the benefits of innate self-DNA sensing through cGAS by facilitating the recognition of cellular damage and indirectly, the presence of pathogens. Likewise, cGAS and STING have proven to be a central element in both iatrogenic and naturally occurring antitumor immunity and in promoting cellular senescence. However, the inflammatory consequences of the cGAS-STING pathway can also become maladaptive through the potentiation of tissue destruction or through the initiation of more subtle forms of chronic inflammatory diseases.

The broad biological roles of intracellular DNA sensing create new opportunities for the exploration and therapeutic manipulation for the prevention and treatment of multiple human diseases. Initial successes with therapies targeting the immunostimulatory effects of the cGAS-STING pathway suggest a major clinical impact in areas of cancer immunotherapy and vaccine development. Furthermore, pharmacological interventions aimed at antagonizing cGAS or STING functions hold similar promise, not only in the context of classical autoinflammatory conditions, but also in the treatment of more complex diseases. We are optimistic that an improved understanding of the molecular basis of innate DNA sensing and signaling via cGAS and STING will aid the design of new …