The Evolution of STING Signaling and Its Involvement in Cancer

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been primarily characterized as an inflammatory mechanism in higher eukaryotes in response to cytosolic double-stranded DNA (dsDNA). Since its initial discovery, detailed mechanisms delineating the dynamic subcellular localization of its different components and downstream signaling have been uncovered, leading to attempts to harness its proinflammatory properties for therapeutic benefit in cancer. Emerging evidence, however, indicates that a crucial primordial function of STING is to promote autophagy, and that downstream interferon (IFN) signaling emerged recently in its evolutionary history. Furthermore, studies suggest that this pathway is a crucial regulator of cellular metabolism that potentially couples inflammation to nutrient availability. We focus on the evolutionarily conserved functions of STING, and we discuss how a broader understanding of this pathway can help us to better appreciate its potential role in cancer and harness it for therapeutic benefit.