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cGAS and cancer therapy: a double-edged sword

Acta Pharmacologica Sinica volume 43, pages 2202–2211 (2022)Cite this article

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.

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Fig. 1: The human cGAS protein structure.
Fig. 2: The cGAS-STING signaling pathway.
Fig. 3: The antitumor functions of cGAS-STING.
Fig. 4: The tumor-promoting roles of cGAS–STING.

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Acknowledgements

This work was supported by a grant from the National Natural Science Foundation of China (81830107) to Qiao-jun He., a grant from the National Natural Science Foundation of China (81773753) to Bo Yang, and a grant from the Natural Science Foundation of Zhejiang Province (LR19H310002) to Hong Zhu. No potential conflicts of interest were disclosed.

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  1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Jia-min Du, Mei-jia Qian, Tao Yuan, Qiao-jun He, Bo Yang & Hong Zhu

  2. Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China

    Rui-han Chen & Qi Ling

  3. The Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, 310024, China

    Qiao-jun He & Hong Zhu

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  7. Qi Ling
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  8. Hong Zhu
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Contributions

HZ and QL conceived and designed the concept of this review article. QJH and BY amended the manuscript. JMD wrote the manuscript. MJQ, TY, and RHC collected the related research articles and reviews. All authors reviewed and approved the manuscript.

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Correspondence to Qi Ling or Hong Zhu.

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The authors declare no competing interests.

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Du, Jm., Qian, Mj., Yuan, T. et al. cGAS and cancer therapy: a double-edged sword. Acta Pharmacol Sin 43, 2202–2211 (2022). https://doi.org/10.1038/s41401-021-00839-6

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  • DOI: https://doi.org/10.1038/s41401-021-00839-6

Keywords

  • cGAS; tumor suppression; tumor promotion; cancer therapy

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