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.

Keywords: Antitumor response; Cancer development; Innate immunity; STING agonists; Type I interferon; cGAS-STING.

Fig. 1

The cGAS-STING DNA sensing signaling pathway. Various DNA derived from virus, dying tumor cells or nucleus and mitochondria binds to and activates the cytosolic DNA sensor cGAS, cGAS catalyzes the synthesis of 2′3′-cGAMP in the presence of ATP and GTP, then 2′3′-cGAMP binds to the ER adaptor STING, which also can be activated by CDNs derived from bacteria. Upon activation, STING translocates from ER to Golgi compartments, where it activates TBK1 and IKK, which phosphorylate IRF3 and IκBα respectively. Then IRF3 and IκBα dimerize and enter nucleus, initiating the transcription of Type I IFN, TNF and IL6. The primary roles of these cytokines are reflected in host defense, inflammation and antitumor immunity

Fig. 2

The antitumor immunity effect of the cGAS-STING pathway. DNA damage leads to the formation of dsDNA in tumor cells, upon its stimulation, STING signaling is activated and promotes the release of Type I IFN, which is crucial for DC maturation. STING signaling activation in DCs is the core step of the whole cancer-immunity cycle, which can be initiated through engulfment of dying/damaged tumor cells, exosome transfer and cGAMP gap junctions. Then DCs migrate towards the tumor-draining lymph node and cross-prime tumor specific CD8⁺ T cells with the help of Type I IFNs. Finally, T cells undergo clonal expansion and traffic through the blood vessel to conduct tumor killing

Fig. 3

The protumor role of the cGAS-STING signaling pathway. A Chronic activation of STING creates an immunosuppressive tumor microenvironment. Continuous STING activation in turn impedes the original antitumor immunity by increasing the infiltration of MDSCs, Tregs and expression of PD-L1, IDO and CCR2, while decreasing the infiltration of NK cells, DCs and T cells. B The function of the STING signaling in tumor metastasis. B-1 delineates the cell autonomous pro-metastasis effect, and B-2, B-3 depict the cell nonautonomous pro-metastasis effect