Targeting the loss of cGAS/STING signaling in cancer

Abstract

The cGAS/STING pathway provides a key host defense mechanism by detecting the accumulation of cytoplasmic double-stranded DNA (dsDNA) and mediating innate and adaptive immune signaling. In addition to detecting pathogen-derived dsDNA, cGAS senses intrinsic dsDNA, such as those associated with defective cell cycle progression and mitophagy that has leaked from the nucleus or mitochondria, and subsequently evokes host immunity to eliminate pathogenic cells. In cancer cells, dysregulation of DNA repair and cell cycle caused at the DNA replication checkpoint and spindle assembly checkpoint results in aberrant cytoplasmic dsDNA accumulation, stimulating anti-tumor immunity. Therefore, the suppression of cGAS/STING signaling is beneficial for survival and frequently observed in cancer cells as a way to evade detection by the immune system, and is likely to be related to immune checkpoint blockade (ICB) resistance. Indeed, the mechanisms of ICB resistance overlap with those acquired in cancers during immunoediting to evade immune surveillance. This review highlights the current understanding of cGAS/STING suppression in cancer cells and discusses how to establish effective strategies to regenerate effective anti-tumor immunity through reactivation of the cGAS/STING pathway.

Keywords: DNA-damaging agent; STING; anti-tumor immunity; cGAS; epigenetic inhibitor.

FIGURE 1

Overview of the cGAS/STING pathway. cGAS is an innate immune sensor recognizing a diverse array of aberrant cytoplasmic dsDNA, which includes pathogenic DNA and self‐DNA derived from the mitochondria or nucleus. Upon binding to cytoplasmic dsDNA, cGAS synthesizes 2′3′‐cGAMP from ATP and GTP as an endogenous second messenger to activate STING. In addition, bacteria‐derived CDNs directly bind to STING. CDN‐binding triggers STING trafficking to the Golgi from ER, and subsequently activates innate immune signaling, leading to antigen presentation and recruitment of cytotoxic T cells.

FIGURE 2

Silencing of the cGAS/STING pathway leading to the evasion of immunosurveillance. Aberrant accumulation of cytoplasmic dsDNA due to genomic instability and mitochondrial defects activates the cGAS/STING pathway, mediating anti‐tumor immunity and also cell autonomous cell death. Therefore, suppression of cGAS and/or STING expression is beneficial for survival from immune pressure caused by pathogenic dsDNA accumulation.

FIGURE 3

Intracellular delivery of synthetic STING agonists. CDN‐type STING agonists exhibit low membrane permeability because of their physiochemical properties, and are likely to be transported into the cytoplasm through endocytosis/pinocytosis or CDN transporters, while non‐CDN‐type small molecule STING agonists show higher membrane permeability.

FIGURE 4

A potential strategy to activate the cGAS/STING pathway by utilizing epigenetic inhibitors and DNA‐damaging agents. Treatment with epigenetic inhibitors targeting DNA methyltransferases and histone methylating/demethylating enzymes upregulates STING expression and derepresses latent retroelement expression. Certain genomic damage such as micronuclei formation following treatment with DNA‐damaging agents causes aberrant accumulation of cytoplasmic dsDNA, leading to anti‐tumor immunity through the activation of the cGAS/STING pathway.