CGAS–STING signalling in cancer: striking a balance with chromosomal instability. (26th April 2023)

• Record Type: Journal Article
• Authors: Beernaert, Bruno; Parkes, Eileen E.
• Is Part Of: Biochemical Society transactions. Volume 51:Number 2(2023)
• Page Start: 539
• Page End: 555
• Publication Date: 2023-04-26
• Subjects: cGAS-STING -- chromosomal instability -- DNA synthesis and repair -- immunosurveillance -- innate immunity; Biochemistry -- Congresses; 572
• DOI: 10.1042/BST20220838
• Languages: English
• ISSNs: 0300-5127

Abstract

Abstract : Chromosomal instability (CIN) is a hallmark of cancer that drives tumour evolution. It is now recognised that CIN in cancer leads to the constitutive production of misplaced DNA in the form of micronuclei and chromatin bridges. These structures are detected by the nucleic acid sensor cGAS, leading to the production of the second messenger 2′3′-cGAMP and activation of the critical hub of innate immune signalling STING. Activation of this immune pathway should instigate the influx and activation of immune cells, resulting in the eradication of cancer cells. That this does not universally occur in the context of CIN remains an unanswered paradox in cancer. Instead, CIN-high cancers are notably adept at immune evasion and are highly metastatic with typically poor outcomes. In this review, we discuss the diverse facets of the cGAS–STING signalling pathway, including emerging roles in homeostatic processes and their intersection with genome stability regulation, its role as a driver of chronic pro-tumour inflammation, and crosstalk with the tumour microenvironment, which may collectively underlie its apparent maintenance in cancers. A better understanding of the mechanisms whereby this immune surveillance pathway is commandeered by chromosomally unstable cancers is critical to the identification of new vulnerabilities for therapeutic exploitation.