Expanding the Role of STING in Cellular Homeostasis and Transformation

Abstract

The cytosolic DNA-sensing cGAS-STING pathway was originally characterized as a key innate immune mediator responsible for the induction of antiviral genes in response to foreign DNA species in the cytosol. Mounting evidence, however, points to a complex role for cGAS and STING in cancer. Two recent reports, by Ranoa et al. (Cancer Research, 2018;https://doi.org/10.1158/0008-5472.CAN-18-1972) and Nassour et al. (Nature 2019;565:659-663), dissect the function of this pathway during the early steps of cellular transformation and shed light on the complexity and context-dependence of cGAS-STING signaling in cancer.

Figure 1.. The Consequences of cGAS–STING Activation Are Highly Dependent on the Status of Downstream Pathways.

(A) In normal proliferating cells, DNA damage and cytosolic DNA arising from chromosome segregation defects activate the cGAS–STING pathway, which in conjunction with p53 signaling promotes p21-dependent cell-cycle arrest. In addition, cytosolic DNA sensing promotes robust type I interferon signaling, leading to activation of cell-mediated immunity. (B) In cells that manage to bypass senescence, STING activation can still promote cell death in response to telomeric damage through the activation of macroautophagy, a process referred to as replicative crisis. (C) In chromosomally unstable cancer cells, however, STING signaling has been shown to promote aggressive tumor cell behavior and metastasis without inducing type I interferon signaling, suggesting that the consequences of cytosolic DNA signaling in cancer are highly dependent on the status of downstream signaling pathways. Abbreviations: cGAS, cyclic GMP-AMP (cGAMP) synthase; CIN, chromosomal instability; IRF3, interferon regulatory factor 3; SASP, senescence-associated secretory phenotype; STING, stimulator of interferon genes.