cGAS-STING signalling in cancer: striking a balance with chromosomal instability

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.

Keywords: DNA synthesis and repair; cGAS-STING; chromosomal instability; immunosurveillance; innate immunity.

Figure 1.. CIN as a driver of cGAS–STING signalling.

Chromosome segregation errors in chromosomally unstable cells can lead to the generation of immunostimulatory genomic dsDNA in the form of micronuclear DNA that becomes exposed to the cytosol upon MN rupture or stretched chromatin in chromatin bridges. Production of 2′3′-cGAMP by cGAS activates STING, which, in turn, activates TBK1. TBK1 phosphorylates the transcription factor IRF3, driving the expression of several type I IFNs. Besides TBK1/IRF3/IFN signalling, STING also instigates NF-κB signalling programs. Canonical NF-κB signalling is triggered through the phosphorylation and suppression of NF-κB inhibitor, alpha (IκBα), releasing the RelA/p50 complex into the nucleus. STING also elicits non-canonical NF-κB signalling through the p100/RelB complex through an as yet poorly understood mechanism. CIN, chromosomal instability; dsDNA, double-stranded DNA; IFN, interferon; MN, micronucleus.

Figure 2.. Cell-intrinsic functions of cGAS and STING in genome stability regulation.

cGAS and STING (both inter- and independently) exert influence over several signalling programs for the regulation of genome stability and cell survival outcomes downstream of CIN. Regulatory functions of cGAS–STING can be beneficial to cell survival and chromosomal stability in the context of lower levels of genomic stress, supporting orderly cell division, DNA repair responses and the autophagic clearance of cytosolic DNA. However, as genotoxic stress increases, cGAS–STING activity skews increasingly towards genome-destabilising, as well as anti-proliferative and pro-apoptotic signalling programs, such as DDR inhibition, senescence and autophagic and mitotic death, pushing cells past the tolerable CIN threshold and restricting the propagation of cells with excessively unstable genomes. DDR, DNA damage response; dsDNA, double-stranded DNA; MN, micronucleus; SASP, senescence-associated secretory phenotype.

Figure 3.. The dichotomous role of CIN-driven cell-intrinsic cGAS–STING inflammatory signalling in cancer.

Activation of cGAS–STING-dependent inflammatory signalling downstream of CIN can exert both tumour-suppressive, as well as tumour-promoting effects in a cell-intrinsic manner. Expression of type I IFNs and downstream engagement of IFNAR/STAT1 induces the expression of multiple effectors, including pro-apoptotic and anti-proliferative genes, that are detrimental to tumour cell survival. Conversely, cGAS–STING-dependent activation of NC-NF-κB signalling can drive IL6/STAT3 signalling and EMT programs, which promote tumour growth and metastasis, respectively. Induction of protective pathways associated with chronic cGAS–STING activity, such as the IRDS and NC-NF-κB signalling can also directly antagonise type I IFN activation, dampening the overtly tumour-suppressive effects of cGAS–STING. IFN, interferon; IFNAR, IFN receptor; IL-6R, IL-6 receptor; IRDS, IFN-related DNA damage resistance signature; MN, micronucleus; NC-NF-κB, non-canonical NF-κB.

Figure 4.. Genetic context and degree of CIN dictate cGAS–STING signalling outcomes.

The cGAS–STING pathway triggers multiple signalling programs in a cell-autonomous manner, which can produce opposing effects on tumour cell fitness. Whether engagement of the cGAS–STING axis results in an outcome that is beneficial or detrimental to tumour cell survival depends on the cumulative status of its downstream pathway components. Highly chromosomally unstable tumours likely acquire adaptations that enable them to avoid activation of overtly anti-proliferative and/or pro-apoptotic signalling programs, such as the senescence program, telomere crisis and type I IFN signalling, and further enhance the beneficial effects of pro-tumour programs. In addition, the fitness costs imparted by CIN-associated stresses may increase the reliance of high CIN tumours on the genome-stabilising effects and pro-survival programs induced by cGAS–STING. As such, chromosomally unstable cancers may tip the balance between beneficial and detrimental cGAS–STING signalling outcomes downstream of CIN in their favour. CIN, chromosomal instability; DDR, DNA damage response; dsDNA, double-stranded DNA; IFN, interferon.

Figure 5.. The pro-tumour functions of cGAS–STING signal transmission in the TME.

(a) Intercellular routes through which mediators of cGAS–STING signalling, predominantly in the form of cGAMP or dsDNA, can be propagated into neighbouring (via cell–cell contacts) or more distant cells (via the extracellular space) of the TME to shape the tumour landscape. (b) Reported functions of cGAS–STING signalling in the establishment of an immune-suppressive pro-tumour TME which may be at play in CIN tumour settings. CAF, cancer-associated fibroblast; CIN, chromosomal instability; dsDNA, double-stranded DNA; IFN, interferon; MDSC, myeloid-derived suppressor cell; SASP, senescence-associated secretory phenotype; TAM, tumour-associated macrophage; TME, tumour microenvironment; Treg, regulatory T cell.