cGAS-STING pathway in oncogenesis and cancer therapeutics

Brandon Yi Da Hoong _, Yunn Hwen Gan, Haiyan Liu and Ee Sin Chen

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Oncotarget. 2020; 11:2930-2955. https://doi.org/10.18632/oncotarget.27673

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Brandon Yi Da Hoong1,2,3, Yunn Hwen Gan1,2,5, Haiyan Liu2,4 and Ee Sin Chen1,2,5

1 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

2 National University Health System (NUHS), Singapore

3 Wong Hock Boon Society, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

4 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

5 NUS Graduate School of Integrative Sciences & Engineering (NGS), National University of Singapore, Singapore

Correspondence to:

Brandon Yi Da Hoong,email: brandon.hoong@u.nus.edu
Ee Sin Chen,email: bchces@nus.edu.sg

Keywords: cyclic GMP-AMP synthase; stimulator of interferon; cGAS; STING; interferon

Received: March 30, 2020     Accepted: June 20, 2020     Published: July 28, 2020


The host innate immunity offers the first line of defense against infection. However, recent evidence shows that the host innate immunity is also critical in sensing the presence of cytoplasmic DNA derived from genomic instability events, such as DNA damage and defective cell cycle progression. This is achieved through the cyclic GMP-AMP synthase (cGAS)/Stimulator of interferon (IFN) genes (STING) pathway. Here we discuss recent insights into the regulation of this pathway in cancer immunosurveillance, and the downstream signaling cascades that coordinate immune cell recruitment to the tumor microenvironment to destroy transformed cells through cellular senescence or cell death programs. Its central role in immunosurveillance positions the cGAS-STING pathway as an attractive anti-cancer immunotherapeutic drug target for chemical agonists or vaccine adjuvants and suggests a key node to be targeted in a synthetic lethal approach. We also discuss adaptive mechanisms used by cancer cells to circumvent cGAS-STING signaling and present evidence linking chronic cGAS-STING activation to inflammation-induced carcinogenesis, cautioning against the use of activating the cGAS-STING pathway as an anti-tumor immunotherapy. A deeper mechanistic understanding of the cGAS-STING pathway will aid in the identification of potentially efficacious anti-cancer therapeutic targets.

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