Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy

Abstract

Cellular recognition of microbial DNA is an evolutionarily conserved mechanism by which the innate immune system detects pathogens. Cyclic GMP-AMP synthase (cGAS) and its downstream effector, stimulator of interferon genes (STING), are involved in mediating fundamental innate antimicrobial immunity by promoting the release of type I interferons (IFNs) and other inflammatory cytokines. Accumulating evidence suggests that the activation of the cGAS-STING axis is critical for antitumor immunity. The downstream cytokines regulated by cGAS-STING, especially type I IFNs, serve as bridges connecting innate immunity with adaptive immunity. Accordingly, a growing number of studies have focused on the synthesis and screening of STING pathway agonists. However, chronic STING activation may lead to a protumor phenotype in certain malignancies. Hence, the cGAS-STING signaling pathway must be orchestrated properly when STING agonists are used alone or in combination. In this review, we discuss the dichotomous roles of the cGAS-STING pathway in tumor development and the latest advances in the use of STING agonists.

Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway

“…We observed that STING pathway activation in leukemia cells resulted in the generation of ROS, which could be a main executor of the cytotoxicity induced by autophagosome inhibitors. STING pathway activation can stimulate IκB kinase and TANK-binding kinase 1 to activate two distinct transcription factors, NF-κB and IRF3, respectively, and both these factors can induce the expression of several antimicrobial and inflammation-related molecules, including ROS 20 – 22 . We observed that an autophagosome inhibitor enhanced the gene expression of TNF-α , IL-12 , and MCP-1 , in a STING pathway-dependent manner.…”

TREX1 as a Novel Immunotherapeutic Target

“…TREX1 and the cGAS-STING pathway have been implicated in the tumor microenvironment [reviewed in refs ( 39 – 45 )]. TREX1 activity has been negatively correlated with outcomes in multiple cancers ( 46 – 48 ).…”

Negative Regulation of the Innate Immune Response through Proteasomal Degradation and Deubiquitination

“…In addition to cGAMP-generated cyclic di-nucleotides, the STING signaling axis is also activated by other stimuli such as cyclic di-nucleotides produced by bacteria, mitochondrial DNA, cytosolic chromatin, and micronuclei [ 154 ]. Activated STING translocates from the ER to the Golgi, where it recruits TBK1 and multimerizes, forming the STING-signalosome [ 155 , 156 ].…”