cGAS and cancer therapy: a double-edged sword

Abstract

Cyclic guanosine monophosphate-adenosine monophosphate adenosine synthetase (cGAS) is a DNA sensor that detects and binds to cytosolic DNA to generate cyclic GMP-AMP (cGAMP). As a second messenger, cGAMP mainly activates the adapter protein STING, which induces the production of type I interferons (IFNs) and inflammatory cytokines. Mounting evidence shows that cGAS is extensively involved in the innate immune response, senescence, and tumor immunity, thereby exhibiting a tumor-suppressive function, most of which is mediated by the STING pathway. In contrast, cGAS can also act as an oncogenic factor, mostly by increasing genomic instability through inhibitory effects on DNA repair, suggesting its utility as an antitumor target. This article reviews the roles and the underlying mechanisms of cGAS in cancer, particularly focusing on its dual roles in carcinogenesis and tumor progression, which are probably attributable to its classical and nonclassical functions, as well as approaches targeting cGAS for cancer therapy.

Keywords: cGAS; tumor suppression; tumor promotion; cancer therapy.

Fig. 1. The human cGAS protein structure.

The human cGAS primary sequence contains 522 amino acids, with a non-conserved N terminus and a conserved Mab21 domain in the C terminus. The protein spine (K187 and L195 in yellow), catalytic sites (E225, D227, and D319 in green) and zinc ribbon (H390, C396, C397, and C404 in red) contribute to the function of cGAS. The structure of human cGAS is from the Protein Data Bank, https://www.rcsb.org/3d-view/6CTA

Fig. 2. The cGAS-STING signaling pathway.

As a DNA sensor, cGAS recognizes foreign, and self-dsDNA to form a 2:2 complex and converts ATP and GTP into cGAMP. cGAMP stimulates STING and promotes the transport of STING from the ER to the Golgi. Then, STING initiates a series of downstream kinase cascade reactions to activate IRF3 and NF-κB. In the nucleus, these reactions stimulate the transcriptional expression of SASP-related molecules, type I interferon, cytokines, etc. The function of cGAS is regulated by a variety of posttranslational modifications: AKT and BLK phosphorylate cGAS; TTLL4/TTLL6 and CCP5/CCP6 regulate glutamylation of cGAS; and RNF185 and TRIM 38 mediate ubiquitination and SUMOylation

Fig. 3. The antitumor functions of cGAS-STING.

① Tumor-derived cGAMP and DNA can activate APCs, which triggers the cGAS-STING pathway and promotes activation of immune cells that function against tumors. ② Upregulation of SASP molecule expression enhances senescence and changes the tissue immune microenvironment to eliminate tumors. ③ Increased levels of LC3 and p62 puncta improve autophagy in tumors through activation of the cGAS-STING pathway. ④ DNA damage and chromosome instability in tumor cells activate the cGAS–STING pathway, and IRF3 induces apoptosis in a manner dependent on the proapoptotic proteins Bax and MOMP.

Fig. 4. The tumor-promoting roles of cGAS–STING.

① Continuous and chronic stimulation, in turn, increases the expression of IDO and proinflammatory cytokines to form an immunosuppressive tumor microenvironment.  ② The cGAMP produced in tumor cells can be exported to adjacent astrocytes, ultimately leading to metastasis and tumor growth. ③ In classic functions, chronic activation of cGAS-STING upregulates nonclassical NF-κB signaling and the SASP, and chronic stimulation promotes EMT. ④ Nuclear cGAS inhibits homologous recombination repair by competing with DNA repair elements to promote tumor progression