cGAS-STING, an important pathway in cancer immunotherapy

Jiang et al. Journal of Hematology & Oncology https://doi.org/10.1186/s13045-020-00916-z (2020) 13:81 REVIEW Open Access cGAS-STING, an important pathway in cancer immunotherapy Minlin Jiang1,2, Peixin Chen1,2, Lei Wang1, Wei Li1, Bin Chen1, Yu Liu1,2, Hao Wang1,2, Sha Zhao1, Lingyun Ye1, Yayi He1* and Caicun Zhou1* Abstract Cytosolic DNA sensing, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, is an important novel role in the immune system. Multiple STING agonists were developed for cancer therapy study with great results achieved in pre-clinical work. Recent progress in the mechanical understanding of STING pathway in IFN production and T cell priming, indicates its promising role for cancer immunotherapy. STING agonists coadministrated with other cancer immunotherapies, including cancer vaccines, immune checkpoint inhibitors such as anti-programmed death 1 and cytotoxic T lymphocyte-associated antigen 4 antibodies, and adoptive T cell transfer therapies, would hold a promise of treating medium and advanced cancers. Despite the applications of STING agonists in cancer immunotherapy, lots of obstacles remain for further study. In this review, we mainly examine the biological characters, current applications, challenges, and future directions of cGAS-STING in cancer immunotherapy. Keywords: cGAS-STING, Cancer, Combined therapy, Immunotherapy, STING pathway Background Cancer is one of the major lethal diseases worldwide, with a high morbidity of 18.1 million estimated new diagnosed cases and mortality of 9.6 million deaths in 2018 reported in the Global cancer statistics [1]. Cancer immunotherapy has made a great breakthrough in oncology, and the discovery of immune checkpoint inhibitors (ICIs) was awarded the 2018 Nobel Prize. Although the application of anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) and anti-programmed death 1 (PD-1) therapies has yielded impressive clinical efficacy, response to these methods only presents in a fraction of patients, and recent evidence has suggested some drug-resistant and lethal cases [2, 3]. * Correspondence: ; Minlin Jiang is the first author of this study 1 Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No 507 Zhengmin Road, Shanghai 200433, People’s Republic of China Full list of author information is available at the end of the article The stimulator of interferon genes (STING) is a novel player with pleiotropic effects in the field of the immune system. The discovery of STING as a 42-kDa “dimeric adaptor protein” in 2008 quickly expanded the fields of immunology research as well as cancer immunotherapy [4]. The STING-targeted treatment is a novel candidate for anti-tumor immunotherapy and agents such as ADU-S100(MIW815) (NCT02675439), MK1454(NCT03010176), and E7766(NCT04144140) have been approved for clinical trials to test their capability of mediating cancer progression in human beings. The understanding of the activated STING pathway has made much progress in antitumor responses necessarily via tumor microenvironment (TME) heating-up by interferon (IFN) secretion and lymphocyte infiltration, which is an excitingly promising direction for cancer immunotherapy (Fig. 1). Several excellent reviews showed unique perspectives on the cyclic GMP-AMP synthase (cGAS)-STING pathway, which identify the structural biology of STING protein, its role in the immune system, as well as the regulation and function of it in DNA sensing [5–7]. In this review, we focus on the © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Jiang et al. Journal of Hematology & Oncology (2020) 13:81 Page 2 of 11 Fig. 1 Timeline of the understanding of STING pathway and its role in cancer immunotherapy. Abbreviation: DMXAA: dimethyloxoxanthenyl acetic acid; FAA: Flavone 8-acetic acid; IRF: interferon regulatory factor; TBK1: TANK-binding kinase 1 basis of the application and pharmacological effect of STING agonists as antitumor therapy, the application of STING in antitumor immunotherapy, its limitations, and some feasible suggestions in the use of STING agonists. Basis of STING signaling pathway cGAS-STING pathway The cGAS-STING pathway is the central cellular cytosolic double-stranded DNA (dsDNA) sensor, allowing innate immune to respond to infections, inflammation, and cancer [8, 9]. Both intrinsic and extrinsic self-DNA sensing can contribute to its activation. It is clear that the STING pathway is more than just important in pathogen detection, but also plays an important role in the detection of rather the self-DNA released from tumor cells and dying cells [10]. It was also reported that the mitochondrial DNA (mtDNA) instability promoted the escape of mtDNA into the cytosol and activated the antiviral immunity via the cGAS-STING pathway [11]. The upstream dsDNA interacts with enzyme cGAS in a sequence-independent way [12, 13], promoting a conformational change of cGAS to catalyze the formation of 2′,3′-cyclic GMP-AMP (cGAMP), a cyclic dinucleotide (CDN) from ATP and GTP, containing the phosphodiester linkages of both 2′–5′ and 3′–5′ [14]. The cGAS activation as well as cGAMP synthase activate protein STING, in which the STING undergoes endoplasmic reticulum (ER)-to-Golgi trafficking and tetramer formation via a higher-order oligomerization [15] (Fig. 2). Palmitoylation of STING in Golgi is proposed for TANK binding kinase 1 (TBK1) as well as interferon regulatory factor 3 (IRF3) recruitment. The STING tetramerization induces recruitment and activation of TBK1 dimers, and TBK1 transphosphorylate STING at its C-terminal domains for IRF3 activation [16]. The IRF3 then displaces to the nucleus and induces immune-stimulated genes (ISG) and type I IFN expression [13]. The NF-κB signaling can also be activated by STING (Fig. 2). Biology and expression of protein STING and its pathway The structur (...truncated)