Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy
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REVIEW
Open Access
Comprehensive elaboration of the cGASSTING signaling axis in cancer development and immunotherapy Juyan Zheng1,2†, Junluan Mo3†, Tao Zhu1,2, Wei Zhuo1,2, Yueneng Yi4, Shuo Hu5, Jiye Yin1,2, Wei Zhang1,2, Honghao Zhou1,2 and Zhaoqian Liu1,2*
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: cGAS-STING, Innate immunity, Type I interferon, STING agonists, Antitumor response, Cancer development
Introduction The discovery of phagocytosis in 1883 advanced the understanding of innate immunity, the first line of host defenses against infection by various pathogens [1]. Protection against infection depends on patternrecognition receptors (PRRs), which recognize microbial products, coordinate antimicrobial defenses and activate * Correspondence: [email protected] † Juyan Zheng and Junluan Mo contributed equally to this work. 1 Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of China 2 Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha 410078, People’s Republic of China Full list of author information is available at the end of the article
adaptive immunity [2]. Abnormal RNA or DNA, RNADNA hybridization and cyclic dinucleotides derived from microbes are usually considered pathogen-associated molecular patterns (PAMPs) [2, 3]. Cells associated with innate immunity recognize different microbial PAMPs through specific PRRs, thereby playing key roles in host resistance to microbial infection [4]. The pathways governing RNA recognition, such as retinoid acid inducible gene I (RIG-I)-like receptors, have been reviewed elsewhere and will not be covered herein. In the case of DNA recognition, one of the best known PRRs is Toll-like receptor 9 (TLR9), which sens
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