Multilayered interplay between the cGAS-STING pathway and autophagy

Abstract

ABSTRACT The cGAS-STING pathway detects cytosolic dsDNA to initiate innate immune responses, serving as a critical surveillance system against infection and cellular stress. Autophagy is an evolutionarily conserved catabolic process that maintains homeostasis by degrading cytoplasmic components. Although these two systems operate through distinct mechanisms, recent studies have uncovered a complex bidirectional regulatory network that intimately links them. On the one hand, STING has an evolutionarily conserved capacity to induce TBK1-independent noncanonical autophagy, and recent studies further link this activity to TFEB-dependent lysosome biogenesis, expanding its functional repertoire beyond classical interferon induction. On the other hand, autophagy restricts cGAS-STING signaling by clearing cytosolic DNA and selectively degrading pathway components, thereby preventing excessive inflammation. Furthermore, mitophagy curtails the release of mitochondrial DNA, a potent cGAS agonist, and recent studies further implicate lysosomes as active signaling platforms associated with mtDNA release, LRRK2 activation, and STING-dependent NF-κB responses. In this review, we discuss recent advances in understanding how the cGAS-STING pathway and autophagy mutually regulate each other at the cellular level, focusing on the molecular mechanisms of this interplay, both canonical and noncanonical, and highlighting how their crosstalk shapes cellular homeostasis and stress adaptation.