New frontiers in the cGAS-STING intracellular DNA-sensing pathway

• Published in: Immunity (Cambridge, Mass.) Vol. 57; no. 4; pp. 718 - 730
• Main Authors: Dvorkin, Steve, Cambier, Stephanie, Volkman, Hannah E., Stetson, Daniel B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.04.2024
• Subjects: antiviral immunity; cGAMP; cGAS; DNA; Immunity, Innate; interferons; Nucleotidyltransferases - metabolism; Signal Transduction; STING; cGAS; STING; antiviral immunity; interferons; cGAMP
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2024.02.019

The cGAS-STING intracellular DNA-sensing pathway has emerged as a key element of innate antiviral immunity and a promising therapeutic target. The existence of an innate immune sensor that can be activated by any double-stranded DNA (dsDNA) of any origin raises fundamental questions about how cGAS is regulated and how it responds to “foreign” DNA while maintaining tolerance to ubiquitous self-DNA. In this review, we summarize recent evidence implicating important roles for cGAS in the detection of foreign and self-DNA. We describe two recent and surprising insights into cGAS-STING biology: that cGAS is tightly tethered to the nucleosome and that the cGAMP product of cGAS is an immunotransmitter acting at a distance to control innate immunity. We consider how these advances influence our understanding of the emerging roles of cGAS in the DNA damage response (DDR), senescence, aging, and cancer biology. Finally, we describe emerging approaches to harness cGAS-STING biology for therapeutic benefit. The cGAS-STING pathway detects intracellular DNA and activates a potent antiviral response. Dvorkin and colleagues summarize recent insights into cGAS-STING biology and its role in host defense, immunopathologies, and anti-tumor immunity.