Interrupting cyclic dinucleotide-cGAS–STING axis with small molecules
The cyclic dinucleotide-cGAS–STING axis plays important roles in host immunity. Activation of this signaling pathway, via cytosolic sensing of bacterial-derived c-di-GMP/c-di-AMP or host-derived cGAMP, leads to the production of inflammatory interferons and cytokines that help resolve infection. Small molecule activators of the cGAS–STING axis have the potential to augment immune response against various pathogens or cancer. The aberrant activation of this pathway, due to gain-of-function mutations in any of the proteins that are part of the signaling axis, could lead to various autoimmune diseases. Inhibiting various nodes of the cGAS–STING axis could provide relief to patients with autoimmune diseases. Many excellent reviews on the cGAS–STING axis have been published recently, and these have mainly focused on the molecular details of the cGAS–STING pathway. This review however focuses on small molecules that can be used to modulate various aspects of the cGAS–STING pathway, as well as other parallel inflammatory pathways.