Immune Regulation of the cGAS-STING Signaling Pathway in the Tumor Microenvironment and Its Clinical Application

References

• Lei X, Lei Y, Li JK, et al. Immune cells within the tumor microenvironment: biological functions and roles in cancer immunotherapy. Cancer Lett. 2020;470:126–133. doi:10.1016/j.canlet.2019.11.009
   PubMed Web of Science ®Google Scholar
• Marzagalli M, Ebelt ND, Manuel ER. Unraveling the crosstalk between melanoma and immune cells in the tumor microenvironment. Semin Cancer Biol. 2019;59:236–250. doi:10.1016/j.semcancer.2019.08.002
   PubMed Web of Science ®Google Scholar
• Galon J, Bruni D. Tumor Immunology and Tumor Evolution: intertwined Histories. Immunity. 2020;52(1):55–81. doi:10.1016/j.immuni.2019.12.018
   PubMed Web of Science ®Google Scholar
• Bose D. cGAS/STING Pathway in Cancer: jekyll and Hyde Story of Cancer Immune Response. Int J Mol Sci. 2017;18:11. doi:10.3390/ijms18112456
   Web of Science ®Google Scholar
• Hopfner KP, Hornung V. Molecular mechanisms and cellular functions of cGAS-STING signalling. Nat Rev Mol Cell Biol. 2020;21(9):501–521. doi:10.1038/s41580-020-0244-x
   PubMed Web of Science ®Google Scholar
• Saeed A, Ruan X, Guan H, et al. Regulation of cGAS-Mediated Immune Responses and Immunotherapy. Adv Sci. 2020;7(6):1902599. doi:10.1002/advs.201902599
   Web of Science ®Google Scholar
• Zierhut C, Funabiki H. Regulation and Consequences of cGAS Activation by Self-DNA. Trends Cell Biol. 2020;30(8):594–605. doi:10.1016/j.tcb.2020.05.006
   PubMed Web of Science ®Google Scholar
• Deb P, Dai J, Singh S, et al. Triggering of the cGAS-STING Pathway in Human Plasmacytoid Dendritic Cells Inhibits TLR9-Mediated IFN Production. J Immunol. 2020;205(1):223–236. doi:10.4049/jimmunol.1800933
   PubMed Web of Science ®Google Scholar
• Watkins-Schulz R, Tiet P, Gallovic MD, et al. A microparticle platform for STING-targeted immunotherapy enhances natural killer cell- and CD8(+) T cell-mediated anti-tumor immunity. Biomaterials. 2019;205:94–105. doi:10.1016/j.biomaterials.2019.03.011
   PubMed Web of Science ®Google Scholar
• Mantovani A, Marchesi F, Malesci A, et al. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14(7):399–416. doi:10.1038/nrclinonc.2016.217
   PubMed Web of Science ®Google Scholar
• Baumhoer D, Amary F, Flanagan AM. An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing. Genes Chromosomes Cancer. 2019;58(2):88–99. doi:10.1002/gcc.22699
   PubMed Web of Science ®Google Scholar
• Fridman WH, Zitvogel L, Sautes-Fridman C, et al. The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol. 2017;14(12):717–734. doi:10.1038/nrclinonc.2017.101
   PubMed Web of Science ®Google Scholar
• Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–899. doi:10.1016/j.cell.2010.01.025
   PubMed Web of Science ®Google Scholar
• Elinav E, Nowarski R, Thaiss CA, et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013;13(11):759–771. doi:10.1038/nrc3611
   PubMed Web of Science ®Google Scholar
• Gajewski TF, Corrales L. New perspectives on type I IFNs in cancer. Cytokine Growth Factor Rev. 2015;26(2):175–178. doi:10.1016/j.cytogfr.2015.01.001
   PubMed Web of Science ®Google Scholar
• Rautela J, Baschuk N, Slaney CY, et al. Loss of host type-I IFN signaling accelerates metastasis and impairs NK-cell antitumor function in multiple models of breast cancer. Cancer Immunol Res. 2015;3(11):1207–1217. doi:10.1158/2326-6066.CIR-15-0065
   PubMed Web of Science ®Google Scholar
• Sun L, Wu J, Du F, et al. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 2013;339(6121):786–791. doi:10.1126/science.1232458
   PubMed Web of Science ®Google Scholar
• Wang C, Guan Y, Lv M, et al. Manganese Increases the Sensitivity of the cGAS-STING Pathway for Double-Stranded DNA and Is Required for the Host Defense against DNA Viruses. Immunity. 2018;48(4):675–87 e7. doi:10.1016/j.immuni.2018.03.017
   PubMed Web of Science ®Google Scholar
• Zhou W, Whiteley AT, de Oliveira Mann CC, et al. Structure of the Human cGAS-DNA Complex Reveals Enhanced Control of Immune Surveillance. Cell. 2018;174(2):300–11 e11. doi:10.1016/j.cell.2018.06.026
   PubMed Web of Science ®Google Scholar
• Ablasser A, Goldeck M, Cavlar T, et al. cGAS produces a 2ʹ-5ʹ-linked cyclic dinucleotide second messenger that activates STING. Nature. 2013;498(7454):380–384. doi:10.1038/nature12306
   PubMed Web of Science ®Google Scholar
• Pepin G, Gantier MP. cGAS-STING Activation in the Tumor Microenvironment and Its Role in Cancer Immunity. Adv Exp Med Biol. 2017;1024:175–194. doi:10.1007/978-981-10-5987-2_8
   PubMed Web of Science ®Google Scholar
• Civril F, Deimling T, de Oliveira Mann CC, et al. Structural mechanism of cytosolic DNA sensing by cGAS. Nature. 2013;498(7454):332–337. doi:10.1038/nature12305
   PubMed Web of Science ®Google Scholar
• Zhang X, Wu J, Du F, et al. The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop. Cell Rep. 2014;6(3):421–430. doi:10.1016/j.celrep.2014.01.003
   PubMed Web of Science ®Google Scholar
• Andreeva L, Hiller B, Kostrewa D, et al. cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders. Nature. 2017;549(7672):394–398. doi:10.1038/nature23890
   PubMed Web of Science ®Google Scholar
• Shang G, Zhu D, Li N, et al. Crystal structures of STING protein reveal basis for recognition of cyclic di-GMP. Nat Struct Mol Biol. 2012;19(7):725–727. doi:10.1038/nsmb.2332
   PubMed Web of Science ®Google Scholar
• Zhao B, Du F, Xu P, et al. A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1. Nature. 2019;569(7758):718–722. doi:10.1038/s41586-019-1228-x
   PubMed Web of Science ®Google Scholar
• Zhao B, Shu C, Gao X, et al. Structural basis for concerted recruitment and activation of IRF-3 by innate immune adaptor proteins. Proc Natl Acad Sci U S A. 2016;113(24):E3403. doi:10.1073/pnas.1603269113
   PubMed Web of Science ®Google Scholar
• Ablasser A, Chen ZJ. cGAS in action: expanding roles in immunity and inflammation. Science. 2019;363:6431. doi:10.1126/science.aat8657
   Web of Science ®Google Scholar
• Ahn J, Konno H, Barber GN. Diverse roles of STING-dependent signaling on the development of cancer. Oncogene. 2015;34(41):5302–5308. doi:10.1038/onc.2014.457
   PubMed Web of Science ®Google Scholar
• Ahn J, Xia T, Konno H, et al. Inflammation-driven carcinogenesis is mediated through STING. Nat Commun. 2014;5:5166. doi:10.1038/ncomms6166
   PubMed Web of Science ®Google Scholar
• Liu H, Zhang H, Wu X, et al. Nuclear cGAS suppresses DNA repair and promotes tumorigenesis. Nature. 2018;563(7729):131–136. doi:10.1038/s41586-018-0629-6
   PubMed Web of Science ®Google Scholar
• Lemos H, Mohamed E, Huang L, et al. STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation. Cancer Res. 2016;76(8):2076–2081. doi:10.1158/0008-5472.CAN-15-1456
   PubMed Web of Science ®Google Scholar
• Zhang CX, Ye SB, Ni JJ, et al. STING signaling remodels the tumor microenvironment by antagonizing myeloid-derived suppressor cell expansion. Cell Death Differ. 2019;26(11):2314–2328. doi:10.1038/s41418-019-0302-0
   PubMed Web of Science ®Google Scholar
• Mohamed E, Sierra RA, Trillo-Tinoco J, et al. The Unfolded Protein Response Mediator PERK Governs Myeloid Cell-Driven Immunosuppression in Tumors through Inhibition of STING Signaling. Immunity. 2020;52(4):668–82 e7. doi:10.1016/j.immuni.2020.03.004
   PubMed Web of Science ®Google Scholar
• Chandra D, Quispe-Tintaya W, Jahangir A, et al. STING ligand c-di-GMP improves cancer vaccination against metastatic breast cancer. Cancer Immunol Res. 2014;2(9):901–910. doi:10.1158/2326-6066.CIR-13-0123
   PubMed Web of Science ®Google Scholar
• Downey CM, Aghaei M, Schwendener RA, et al. DMXAA causes tumor site-specific vascular disruption in murine non-small cell lung cancer, and like the endogenous non-canonical cyclic dinucleotide STING agonist, 2ʹ3’-cGAMP, induces M2 macrophage repolarization. PLoS One. 2014;9(6):e99988. doi:10.1371/journal.pone.0099988
   PubMed Web of Science ®Google Scholar
• Ma R, Ji T, Chen D, et al. Tumor cell-derived microparticles polarize M2 tumor-associated macrophages for tumor progression. Oncoimmunology. 2016;5(4):e1118599. doi:10.1080/2162402X.2015.1118599
   PubMed Web of Science ®Google Scholar
• An X, Zhu Y, Zheng T, et al. An Analysis of the Expression and Association with Immune Cell Infiltration of the cGAS/STING Pathway in Pan-Cancer. Mol Ther Nucleic Acids. 2019;14:80–89. doi:10.1016/j.omtn.2018.11.003
   PubMedGoogle Scholar
• Shae D, Becker KW, Christov P, et al. Endosomolytic polymersomes increase the activity of cyclic dinucleotide STING agonists to enhance cancer immunotherapy. Nat Nanotechnol. 2019;14(3):269–278. doi:10.1038/s41565-018-0342-5
   PubMed Web of Science ®Google Scholar
• Song S, Peng P, Tang Z, et al. Decreased expression of STING predicts poor prognosis in patients with gastric cancer. Sci Rep. 2017;7:39858. doi:10.1038/srep39858
   PubMed Web of Science ®Google Scholar
• Selvan SR, Dowling JP, Kelly WK, et al. Indoleamine 2,3-dioxygenase (IDO): biology and Target in Cancer Immunotherapies. Curr Cancer Drug Targets. 2016;16(9):755–764. doi:10.2174/1568009615666151030102250
   PubMed Web of Science ®Google Scholar
• Yentz S, Smith D. Indoleamine 2,3-Dioxygenase (IDO) Inhibition as a Strategy to Augment Cancer Immunotherapy. BioDrugs. 2018;32(4):311–317. doi:10.1007/s40259-018-0291-4
   PubMed Web of Science ®Google Scholar
• Prendergast GC, Malachowski WJ, Mondal A, et al. Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer. Int Rev Cell Mol Biol. 2018;336:175–203. doi:10.1016/bs.ircmb.2017.07.004
   PubMed Web of Science ®Google Scholar
• Davar D, Bahary N. Modulating Tumor Immunology by Inhibiting Indoleamine 2,3-Dioxygenase (IDO): recent Developments and First Clinical Experiences. Target Oncol. 2018;13(2):125–140. doi:10.1007/s11523-017-0547-9
   PubMed Web of Science ®Google Scholar
• Hornyak L, Dobos N, Koncz G, et al. The Role of Indoleamine-2,3-Dioxygenase in Cancer Development, Diagnostics, and Therapy. Front Immunol. 2018;9:151. doi:10.3389/fimmu.2018.00151
   PubMed Web of Science ®Google Scholar
• Woo SR, Fuertes MB, Corrales L, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014;41(5):830–842. doi:10.1016/j.immuni.2014.10.017
   PubMed Web of Science ®Google Scholar
• Sen T, Rodriguez BL, Chen L, et al. Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer. Cancer Discov. 2019;9(5):646–661. doi:10.1158/2159-8290.CD-18-1020
   PubMed Web of Science ®Google Scholar
• Li T, Cheng H, Yuan H, et al. Antitumor Activity of cGAMP via Stimulation of cGAS-cGAMP-STING-IRF3 Mediated Innate Immune Response. Sci Rep. 2016;6:19049. doi:10.1038/srep19049
   PubMed Web of Science ®Google Scholar
• Durante M, Formenti SC. Radiation-Induced Chromosomal Aberrations and Immunotherapy: micronuclei, Cytosolic DNA, and Interferon-Production Pathway. Front Oncol. 2018;8:192. doi:10.3389/fonc.2018.00192
   PubMed Web of Science ®Google Scholar
• Deng L, Liang H, Xu M, et al. STING-Dependent Cytosolic DNA sensing promotes radiation-induced type interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014;41(5):843–852. doi:10.1016/j.immuni.2014.10.019
   PubMed Web of Science ®Google Scholar
• Ceron S, North BJ, Taylor SA, et al. The STING agonist 5,6-dimethylxanthenone-4-acetic acid (DMXAA) stimulates an antiviral state and protects mice against herpes simplex virus-induced neurological disease. Virology. 2019;529:23–28. doi:10.1016/j.virol.2019.01.006
   PubMed Web of Science ®Google Scholar
• Corrales L, Glickman LH, McWhirter SM, et al. Direct Activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 2015;11(7):1018–1030. doi:10.1016/j.celrep.2015.04.031
   PubMed Web of Science ®Google Scholar
• Ki HH, Lee JH, Lee HY, et al. Triticum aestivum Sprouts Extract Inhibits Azoymethane (AOM)/Dextran Sodium Sulfate (DSS)-Induced Colon Carcinogenesis in Mice. Nutr Cancer. 2018;70(6):928–937. doi:10.1080/01635581.2018.1490447
   PubMed Web of Science ®Google Scholar
• Campisi J, d’Adda Di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8(9):729–740. doi:10.1038/nrm2233
   PubMed Web of Science ®Google Scholar
• Childs BG, Durik M, Baker DJ, et al. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med. 2015;21(12):1424–1435. doi:10.1038/nm.4000
   PubMed Web of Science ®Google Scholar
• Han X, Chen H, Gong H, et al. Autolysosomal degradation of cytosolic chromatin fragments antagonizes oxidative stress-induced senescence. J Biol Chem. 2020;295(14):4451–4463. doi:10.1074/jbc.RA119.010734
   PubMed Web of Science ®Google Scholar
• Blasiak J. Senescence in the pathogenesis of age-related macular degeneration. Cell Mol Life Sci. 2020;77(5):789–805. doi:10.1007/s00018-019-03420-x
   PubMed Web of Science ®Google Scholar
• Loo TM, Miyata K, Tanaka Y, et al. Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer. Cancer Sci. 2020;111(2):304–311. doi:10.1111/cas.14266
   PubMed Web of Science ®Google Scholar
• Hari P, Millar FR, Tarrats N, et al. The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype. Sci Adv. 2019;5(6):eaaw0254. doi:10.1126/sciadv.aaw0254
   PubMed Web of Science ®Google Scholar
• Ohkuri T, Kosaka A, Ishibashi K, et al. Intratumoral administration of cGAMP transiently accumulates potent macrophages for anti-tumor immunity at a mouse tumor site. Cancer Immunol Immunother. 2017;66(6):705–716. doi:10.1007/s00262-017-1975-1
   PubMed Web of Science ®Google Scholar
• Ohkuri T, Kosaka A, Nagato T, et al. Effects of STING stimulation on macrophages: STING agonists polarize into “classically” or “alternatively” activated macrophages? Hum Vaccin Immunother. 2018;14(2):285–287. doi:10.1080/21645515.2017.1395995
   PubMed Web of Science ®Google Scholar
• Domvri K, Petanidis S, Zarogoulidis P, et al. Treg-dependent immunosuppression triggers effector T cell dysfunction via the STING/ILC2 axis. Clin Immunol. 2020:108620. doi:10.1016/j.clim.2020.108620
   PubMed Web of Science ®Google Scholar
• Benmerzoug S, Rose S, Bounab B, et al. STING-dependent sensing of self-DNA drives silica-induced lung inflammation. Nat Commun. 2018;9(1):5226. doi:10.1038/s41467-018-07425-1
   PubMedGoogle Scholar
• Marcus A, Mao AJ, Lensink-Vasan M, et al. Tumor-Derived cGAMP Triggers a STING-Mediated Interferon Response in Non-tumor Cells to Activate the NK Cell Response. Immunity. 2018;49(4):754–63 e4. doi:10.1016/j.immuni.2018.09.016
   PubMed Web of Science ®Google Scholar
• Lam AR, Bert NL, Ho SS, et al. RAE1 ligands for the NKG2D receptor are regulated by STING-dependent DNA sensor pathways in lymphoma. Cancer Res. 2014;74(8):2193–2203. doi:10.1158/0008-5472.CAN-13-1703
   PubMed Web of Science ®Google Scholar
• Molfetta R, Quatrini L, Santoni A, et al. Regulation of NKG2D-Dependent NK Cell Functions: the Yin and the Yang of Receptor Endocytosis. Int J Mol Sci. 2017;18:8. doi:10.3390/ijms18081677
   Web of Science ®Google Scholar
• Parihar R, Rivas C, Huynh M, et al. NK Cells Expressing a Chimeric Activating Receptor Eliminate MDSCs and Rescue Impaired CAR-T Cell Activity against Solid Tumors. Cancer Immunol Res. 2019;7(3):363–375. doi:10.1158/2326-6066.CIR-18-0572
   PubMed Web of Science ®Google Scholar
• Chen T, Zhang T, Liu C, et al. NK cells suppress CD8(+) T cell immunity via NKG2D in severe aplastic anemia. Cell Immunol. 2019;335:6–14. doi:10.1016/j.cellimm.2018.10.004
   PubMed Web of Science ®Google Scholar
• Bhatelia K, Singh A, Tomar D, et al. Antiviral signaling protein MITA acts as a tumor suppressor in breast cancer by regulating NF-kappaB induced cell death. Biochim Biophys Acta. 2014;1842(2):144–153. doi:10.1016/j.bbadis.2013.11.006
   PubMed Web of Science ®Google Scholar
• Tang CH, Zundell JA, Ranatunga S, et al. Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells. Cancer Res. 2016;76(8):2137–2152. doi:10.1158/0008-5472.CAN-15-1885
   PubMed Web of Science ®Google Scholar
• An M, Yu C, Xi J, et al. Induction of necrotic cell death and activation of STING in the tumor microenvironment via cationic silica nanoparticles leading to enhanced antitumor immunity. Nanoscale. 2018;10(19):9311–9319. doi:10.1039/c8nr01376d
   PubMed Web of Science ®Google Scholar
• Li H, Zhuang Q, Wang Y, et al. HBV life cycle is restricted in mouse hepatocytes expressing human NTCP. Cell Mol Immunol. 2014;11(2):175–183. doi:10.1038/cmi.2013.66
   PubMed Web of Science ®Google Scholar
• Klionsky DJ, Abdelmohsen K, Abe A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016;12(1):1–222. doi:10.1080/15548627.2015.1100356
   PubMed Web of Science ®Google Scholar
• Liang D, Xiao-Feng H, Guan-Jun D, et al. Activated STING enhances Tregs infiltration in the HPV-related carcinogenesis of tongue squamous cells via the c-jun/CCL22 signal. Biochim Biophys Acta. 2015;1852(11):2494–2503. doi:10.1016/j.bbadis.2015.08.011
   PubMed Web of Science ®Google Scholar
• Li N, Zhou H, Wu H, et al. STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3. Redox Biol. 2019;24:101215. doi:10.1016/j.redox.2019.101215
   PubMed Web of Science ®Google Scholar
• Gaidt MM, Ebert TS, Chauhan D, et al. The DNA Inflammasome in human myeloid cells is initiated by a STING-Cell Death Program Upstream of NLRP3. Cell. 2017;171(5):1110–24 e18. doi:10.1016/j.cell.2017.09.039
   PubMed Web of Science ®Google Scholar
• Krzesniak M, Zajkowicz A, Gdowicz-Klosok A, et al. Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity. Cell Signal. 2020;69:109552. doi:10.1016/j.cellsig.2020.109552
   PubMed Web of Science ®Google Scholar
• Gui X, Yang H, Li T, et al. Autophagy induction via STING trafficking is a primordial function of the cGAS pathway. Nature. 2019;567(7747):262–266. doi:10.1038/s41586-019-1006-9
   PubMed Web of Science ®Google Scholar
• Moretti J, Roy S, Bozec D, et al. STING Senses Microbial Viability to Orchestrate Stress-Mediated Autophagy of the Endoplasmic Reticulum. Cell. 2017;171(4):809–23 e13. doi:10.1016/j.cell.2017.09.034
   PubMed Web of Science ®Google Scholar
• Tan YS, Sansanaphongpricha K, Xie Y, et al. Mitigating SOX2-potentiated Immune Escape of Head and Neck Squamous Cell Carcinoma with a STING-inducing Nanosatellite Vaccine. Clin Cancer Res. 2018;24(17):4242–4255. doi:10.1158/1078-0432.CCR-17-2807
   PubMed Web of Science ®Google Scholar
• Demaria O, De Gassart A, Coso S, et al. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc Natl Acad Sci U S A. 2015;112(50):15408–15413. doi:10.1073/pnas.1512832112
   PubMed Web of Science ®Google Scholar
• Vogt D, Zaver S, Ranjan A, et al. STING is dispensable during KSHV infection of primary endothelial cells. Virology. 2020;540:150–159. doi:10.1016/j.virol.2019.11.012
   PubMed Web of Science ®Google Scholar
• Mao Y, Luo W, Zhang L, et al. STING-IRF3 triggers endothelial inflammation in response to free fatty acid-induced mitochondrial damage in diet-induced obesity. Arterioscler Thromb Vasc Biol. 2017;37(5):920–929. doi:10.1161/ATVBAHA.117.309017
   PubMed Web of Science ®Google Scholar
• Guo Y, Gu R, Gan D, et al. Mitochondrial DNA drives noncanonical inflammation activation via cGAS-STING signaling pathway in retinal microvascular endothelial cells. Cell Commun Signal. 2020;18(1):172. doi:10.1186/s12964-020-00637-3
   PubMed Web of Science ®Google Scholar
• Yuan L, Mao Y, Luo W, et al. Palmitic acid dysregulates the Hippo-YAP pathway and inhibits angiogenesis by inducing mitochondrial damage and activating the cytosolic DNA sensor cGAS-STING-IRF3 signaling mechanism. J Biol Chem. 2017;292(36):15002–15015. doi:10.1074/jbc.M117.804005
   PubMed Web of Science ®Google Scholar
• Ishikawa H, Ma Z, Barber GN. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature. 2009;461(7265):788–792. doi:10.1038/nature08476
   PubMed Web of Science ®Google Scholar
• Liu Y, Jesus AA, Marrero B, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371(6):507–518. doi:10.1056/NEJMoa1312625
   PubMed Web of Science ®Google Scholar
• Warner JD, Irizarry-Caro RA, Bennion BG, et al. STING-associated vasculopathy develops independently of IRF3 in mice. J Exp Med. 2017;214(11):3279–3292. doi:10.1084/jem.20171351
   PubMed Web of Science ®Google Scholar
• Ching LM, Cao Z, Kieda C, et al. Induction of endothelial cell apoptosis by the antivascular agent 5,6-Dimethylxanthenone-4-acetic acid. Br J Cancer. 2002;86(12):1937–1942. doi:10.1038/sj.bjc.6600368
   PubMed Web of Science ®Google Scholar
• Gao P, Ascano M, Zillinger T, et al. Structure-function analysis of STING activation by c[G(2ʹ,5ʹ)pA(3ʹ,5ʹ)p] and targeting by antiviral DMXAA. Cell. 2013;154(4):748–762. doi:10.1016/j.cell.2013.07.023
   PubMed Web of Science ®Google Scholar
• Daei Farshchi Adli A, Jahanban-Esfahlan R, Seidi K, et al. An overview on Vadimezan (DMXAA): the vascular disrupting agent. Chem Biol Drug Des. 2018;91(5):996–1006. doi:10.1111/cbdd.13166
   PubMed Web of Science ®Google Scholar
• Yang H, Lee WS, Kong SJ, et al. STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade. J Clin Invest. 2019;129(10):4350–4364. doi:10.1172/JCI125413
   PubMed Web of Science ®Google Scholar
• He L, Xiao X, Yang X, et al. STING signaling in tumorigenesis and cancer therapy: a friend or foe? Cancer Lett. 2017;402:203–212. doi:10.1016/j.canlet.2017.05.026
   PubMed Web of Science ®Google Scholar
• Chen Q, Boire A, Jin X, et al. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature. 2016;533(7604):493–498. doi:10.1038/nature18268
   PubMed Web of Science ®Google Scholar
• Hou Y, Liang H, Rao E, et al. Non-canonical NF-kappaB Antagonizes STING Sensor-Mediated DNA Sensing in Radiotherapy. Immunity. 2018;49(3):490–503 e4. doi:10.1016/j.immuni.2018.07.008
   PubMed Web of Science ®Google Scholar
• Klarquist J, Hennies CM, Lehn MA, et al. STING-mediated DNA sensing promotes antitumor and autoimmune responses to dying cells. J Immunol. 2014;193(12):6124–6134. doi:10.4049/jimmunol.1401869
   PubMed Web of Science ®Google Scholar
• Munn DH, Mellor AL. IDO in the Tumor Microenvironment: inflammation, Counter-Regulation, and Tolerance. Trends Immunol. 2016;37(3):193–207. doi:10.1016/j.it.2016.01.002
   PubMed Web of Science ®Google Scholar
• Bakhoum SF, Ngo B, Laughney AM, et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature. 2018;553(7689):467–472. doi:10.1038/nature25432
   PubMed Web of Science ®Google Scholar
• Xu X, Li M, Wu Z, et al. Endoplasmic Reticulum Transmembrane Proteins ZDHHC1 and STING Both Act as Direct Adaptors for IRF3 Activation in Teleost. J Immunol. 2017;199(10):3623–3633. doi:10.4049/jimmunol.1700750
   PubMed Web of Science ®Google Scholar
• Kranzusch PJ, Lee AS, Berger JM, et al. Structure of human cGAS reveals a conserved family of second-messenger enzymes in innate immunity. Cell Rep. 2013;3(5):1362–1368. doi:10.1016/j.celrep.2013.05.008
   PubMed Web of Science ®Google Scholar
• Lv M, Chen M, Zhang R, et al. Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy. Cell Res. 2020;30(11):966–979. doi:10.1038/s41422-020-00395-4
   PubMed Web of Science ®Google Scholar
• Hou L, Tian C, Yan Y, et al. Manganese-based nanoactivator optimizes cancer immunotherapy via enhancing innate immunity. ACS Nano. 2020;14(4):3927–3940. doi:10.1021/acsnano.9b06111
   PubMed Web of Science ®Google Scholar
• Wang M, Sooreshjani MA, Mikek C, et al. Suramin potently inhibits cGAMP synthase, cGAS, in THP1 cells to modulate IFN-beta levels. Future Med Chem. 2018;10(11):1301–1317. doi:10.4155/fmc-2017-0322
   PubMed Web of Science ®Google Scholar
• An J, Woodward JJ, Sasaki T, et al. Cutting edge: antimalarial drugs inhibit IFN-beta production through blockade of cyclic GMP-AMP synthase-DNA interaction. J Immunol. 2015;194(9):4089–4093. doi:10.4049/jimmunol.1402793
   PubMed Web of Science ®Google Scholar
• Piscianz E, Cuzzoni E, Sharma R, et al. Reappraisal of Antimalarials in Interferonopathies: new Perspectives for Old Drugs. Curr Med Chem. 2018;25(24):2797–2810. doi:10.2174/0929867324666170911162331
   PubMed Web of Science ®Google Scholar
• Liu J, Wu X, Wang H, et al. HFE inhibits type I IFNs signaling by targeting the SQSTM1-mediated MAVS autophagic degradation. Autophagy. 2020:1–16. doi:10.1080/15548627.2020.1804683
   PubMedGoogle Scholar
• Liu ZS, Cai H, Xue W, et al. G3BP1 promotes DNA binding and activation of cGAS. Nat Immunol. 2019;20(1):18–28. doi:10.1038/s41590-018-0262-4
   PubMed Web of Science ®Google Scholar
• Zhang CH, Wang JX, Cai ML, et al. The roles and mechanisms of G3BP1 in tumour promotion. J Drug Target. 2019;27(3):300–305. doi:10.1080/1061186X.2018.1523415
   PubMed Web of Science ®Google Scholar
• Shim JH, Su ZY, Chae JI, et al. Epigallocatechin gallate suppresses lung cancer cell growth through Ras-GTPase-activating protein SH3 domain-binding protein 1. Cancer Prev Res. 2010;3(5):670–679. doi:10.1158/1940-6207.CAPR-09-0185
   PubMed Web of Science ®Google Scholar
• Du XX, Su XD. Detection of Cyclic Dinucleotides by STING. Methods Mol Biol. 2017;1657:59–69. doi:10.1007/978-1-4939-7240-1_6
   PubMedGoogle Scholar
• Burdette DL, Monroe KM, Sotelo-Troha K, et al. STING is a direct innate immune sensor of cyclic di-GMP. Nature. 2011;478(7370):515–518. doi:10.1038/nature10429
   PubMed Web of Science ®Google Scholar
• Sintim HO, Mikek CG, Wang M, et al. Interrupting cyclic dinucleotide-cGAS-STING axis with small molecules. Medchemcomm. 2019;10(12):1999–2023. doi:10.1039/c8md00555a
   PubMed Web of Science ®Google Scholar
• Konno H, Konno K, Barber GN. Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell. 2013;155(3):688–698. doi:10.1016/j.cell.2013.09.049
   PubMed Web of Science ®Google Scholar
• Morehouse BR, Govande AA, Millman A, et al. STING cyclic dinucleotide sensing originated in bacteria. Nature. 2020;586(7829):429–433. doi:10.1038/s41586-020-2719-5
   PubMed Web of Science ®Google Scholar
• Thomsen MK, Skouboe MK, Boularan C, et al. The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma. Oncogene. 2020;39(8):1652–1664. doi:10.1038/s41388-019-1108-8
   PubMed Web of Science ®Google Scholar
• Pollock AJ, Zaver SA, Woodward JJ. A STING-based biosensor affords broad cyclic dinucleotide detection within single living eukaryotic cells. Nat Commun. 2020;11(1):3533. doi:10.1038/s41467-020-17228-y
   PubMed Web of Science ®Google Scholar
• Kwon Y, Park OJ, Kim J, et al. Cyclic Dinucleotides Inhibit Osteoclast Differentiation Through STING-Mediated Interferon-beta Signaling. J Bone Miner Res. 2019;34(7):1366–1375. doi:10.1002/jbmr.3701
   PubMed Web of Science ®Google Scholar
• Wu JJ, Zhao L, Hu HG, et al. Agonists and inhibitors of the STING pathway: potential agents for immunotherapy. Med Res Rev. 2020;40(3):1117–1141. doi:10.1002/med.21649
   PubMed Web of Science ®Google Scholar
• Liu H, Moura-Alves P, Pei G, et al. cGAS facilitates sensing of extracellular cyclic dinucleotides to activate innate immunity. EMBO Rep. 2019;20:4. doi:10.15252/embr.201846293
   Web of Science ®Google Scholar
• Cui J, Chen Y, Wang HY, et al. Mechanisms and pathways of innate immune activation and regulation in health and cancer. Hum Vaccin Immunother. 2014;10(11):3270–3285. doi:10.4161/21645515.2014.979640
   PubMed Web of Science ®Google Scholar
• Zhu Q, Man SM, Gurung P, et al. Cutting edge: STING mediates protection against colorectal tumorigenesis by governing the magnitude of intestinal inflammation. J Immunol. 2014;193(10):4779–4782. doi:10.4049/jimmunol.1402051
   PubMed Web of Science ®Google Scholar
• Leach DG, Dharmaraj N, Piotrowski SL, et al. STINGel: controlled release of a cyclic dinucleotide for enhanced cancer immunotherapy. Biomaterials. 2018;163:67–75. doi:10.1016/j.biomaterials.2018.01.035
   PubMed Web of Science ®Google Scholar
• Jenal U, Reinders A, Lori C. Cyclic di-GMP: second messenger extraordinaire. Nat Rev Microbiol. 2017;15(5):271–284. doi:10.1038/nrmicro.2016.190
   PubMed Web of Science ®Google Scholar
• Guey B, Ablasser A. A carrier for cyclic dinucleotides. Nat Immunol. 2019;20(11):1418–1420. doi:10.1038/s41590-019-0521-z
   PubMed Web of Science ®Google Scholar
• Berger G, Lawler SE. Novel non-nucleotidic STING agonists for cancer immunotherapy. Future Med Chem. 2018;10(24):2767–2769. doi:10.4155/fmc-2018-0367
   PubMed Web of Science ®Google Scholar
• Curran E, Chen X, Corrales L, et al. STING Pathway Activation Stimulates Potent Immunity against Acute Myeloid Leukemia. Cell Rep. 2016;15(11):2357–2366. doi:10.1016/j.celrep.2016.05.023
   PubMed Web of Science ®Google Scholar
• Rauca VF, Licarete E, Luput L, et al. Combination therapy of simvastatin and 5, 6-dimethylxanthenone-4-acetic acid synergistically suppresses the aggressiveness of B16.F10 melanoma cells. PLoS One. 2018;13(8):e0202827. doi:10.1371/journal.pone.0202827
   PubMed Web of Science ®Google Scholar
• Smolarczyk R, Cichon T, Pilny E, et al. Author Correction: combination of anti-vascular agent - DMXAA and HIF-1alpha inhibitor - digoxin inhibits the growth of melanoma tumors. Sci Rep. 2020;10(1):5698. doi:10.1038/s41598-020-62440-x
   PubMed Web of Science ®Google Scholar
• Ahn J, Barber GN. Self-DNA, STING-dependent signaling and the origins of autoinflammatory disease. Curr Opin Immunol. 2014;31:121–126. doi:10.1016/j.coi.2014.10.009
   PubMed Web of Science ®Google Scholar
• Martin GR, Henare K, Salazar C, et al. Expression of a constitutively active human STING mutant in hematopoietic cells produces an Ifnar1-dependent vasculopathy in mice. Life Sci Alliance. 2019;2:3. doi:10.26508/lsa.201800215
   Web of Science ®Google Scholar
• Pokatayev V, Hasin N, Chon H, et al. RNase H2 catalytic core Aicardi-Goutieres syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice. J Exp Med. 2016;213(3):329–336. doi:10.1084/jem.20151464
   PubMed Web of Science ®Google Scholar
• Haag SM, Gulen MF, Reymond L, et al. Targeting STING with covalent small-molecule inhibitors. Nature. 2018;559(7713):269–273. doi:10.1038/s41586-018-0287-8
   PubMed Web of Science ®Google Scholar
• Le Naour J, Zitvogel L, Galluzzi L, et al. Trial watch: STING agonists in cancer therapy. Oncoimmunology. 2020;9(1):1777624. doi:10.1080/2162402X.2020.1777624
   PubMed Web of Science ®Google Scholar
• Kwon J, Bakhoum SF. The Cytosolic DNA-Sensing cGAS-STING Pathway in Cancer. Cancer Discov. 2020;10(1):26–39. doi:10.1158/2159-8290.CD-19-0761
   PubMed Web of Science ®Google Scholar
• Jiang M, Chen P, Wang L, et al. cGAS-STING, an important pathway in cancer immunotherapy. J Hematol Oncol. 2020;13(1):81. doi:10.1186/s13045-020-00916-z
   PubMed Web of Science ®Google Scholar
• Li A, Yi M, Qin S, et al. Activating cGAS-STING pathway for the optimal effect of cancer immunotherapy. J Hematol Oncol. 2019;12(1):35. doi:10.1186/s13045-019-0721-x
   PubMedGoogle Scholar
• Khoo LT, Chen LY. Role of the cGAS-STING pathway in cancer development and oncotherapeutic approaches. EMBO Rep. 2018;19:12. doi:10.15252/embr.201846935
   Web of Science ®Google Scholar
• Iurescia S, Fioretti D, Rinaldi M. Targeting Cytosolic Nucleic Acid-Sensing Pathways for Cancer Immunotherapies. Front Immunol. 2018;9:711. doi:10.3389/fimmu.2018.00711
   PubMed Web of Science ®Google Scholar
• Lara PN Jr, Douillard JY, Nakagawa K, et al. Randomized Phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer. J Clin Oncol. 2011;29(22):2965–2971. doi:10.1200/JCO.2011.35.0660
   PubMed Web of Science ®Google Scholar
• McKeage MJ. Clinical trials of vascular disrupting agents in advanced non–small-cell lung cancer. Clin Lung Cancer. 2011;12(3):143–147. doi:10.1016/j.cllc.2011.03.010
   PubMed Web of Science ®Google Scholar
• Pan BS, Perera SA, Piesvaux JA, et al. An orally available non-nucleotide STING agonist with antitumor activity. Science. 2020;369(6506):eaba6098. doi:10.1126/science.aba6098
   PubMed Web of Science ®Google Scholar
• Chin EN, Yu C, Vartabedian VF, et al. Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic. Science. 2020;369(6506):993–999. doi:10.1126/science.abb4255
   PubMed Web of Science ®Google Scholar
• Foote JB, Kok M, Leatherman JM, et al. A STING Agonist Given with OX40 Receptor and PD-L1 modulators primes immunity and reduces tumor growth in tolerized mice. Cancer Immunol Res. 2017;5(6):468–479. doi:10.1158/2326-6066.CIR-16-0284
   PubMed Web of Science ®Google Scholar
• Flood BA, Higgs EF, Li S, et al. STING pathway agonism as a cancer therapeutic. Immunol Rev. 2019;290(1):24–38. doi:10.1111/imr.12765
   PubMed Web of Science ®Google Scholar
• Venkatesulu BP, Mallick S, Lin SH, et al. A systematic review of the influence of radiation-induced lymphopenia on survival outcomes in solid tumors. Crit Rev Oncol Hematol. 2018;123:42–51. doi:10.1016/j.critrevonc.2018.01.003
   PubMed Web of Science ®Google Scholar
• Mackenzie KJ, Carroll P, Martin CA, et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature. 2017;548(7668):461–465. doi:10.1038/nature23449
   PubMed Web of Science ®Google Scholar
• Harding SM, Benci JL, Irianto J, et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature. 2017;548(7668):466–470. doi:10.1038/nature23470
   PubMed Web of Science ®Google Scholar
• Baird JR, Friedman D, Cottam B, et al. Radiotherapy Combined with Novel STING-Targeting Oligonucleotides Results in Regression of Established Tumors. Cancer Res. 2016;76(1):50–61. doi:10.1158/0008-5472.CAN-14-3619
   PubMed Web of Science ®Google Scholar
• Wang QT, Nie Y, Sun SN, et al. Tumor-associated antigen-based personalized dendritic cell vaccine in solid tumor patients. Cancer Immunol Immunother. 2020;69(7):1375–1387. doi:10.1007/s00262-020-02496-w
   PubMed Web of Science ®Google Scholar
• He Y, Zhao H, Li XM, et al. Use of mesothelin as a tumor-associated antigen in cervical squamous cell carcinoma. Gene. 2019;690:30–37. doi:10.1016/j.gene.2018.12.029
   PubMed Web of Science ®Google Scholar
• Costa-Nunes C, Cachot A, Bobisse S, et al. High-throughput screening of human tumor antigen-specific CD4 T cells, including neoantigen-reactive T Cells. Clin Cancer Res. 2019;25(14):4320–4331. doi:10.1158/1078-0432.CCR-18-1356
   PubMed Web of Science ®Google Scholar
• Kinkead HL, Hopkins A, Lutz E, et al. Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances antitumor immunity in murine pancreatic cancer. JCI Insight. 2018;3:20. doi:10.1172/jci.insight.122857
   Web of Science ®Google Scholar
• Wang Z, Celis E. STING activator c-di-GMP enhances the anti-tumor effects of peptide vaccines in melanoma-bearing mice. Cancer Immunol Immunother. 2015;64(8):1057–1066. doi:10.1007/s00262-015-1713-5
   PubMed Web of Science ®Google Scholar
• Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27(4):450–461. doi:10.1016/j.ccell.2015.03.001
   PubMed Web of Science ®Google Scholar
• Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med. 2018;378(2):158–168. doi:10.1056/NEJMra1703481
   PubMed Web of Science ®Google Scholar
• Keenan TE, Burke KP, Van Allen EM. Genomic correlates of response to immune checkpoint blockade. Nat Med. 2019;25(3):389–402. doi:10.1038/s41591-019-0382-x
   PubMed Web of Science ®Google Scholar
• McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351(6280):1463–1469. doi:10.1126/science.aaf1490
   PubMed Web of Science ®Google Scholar
• Li B, Chan HL, Chen P. Immune checkpoint inhibitors: basics and challenges. Curr Med Chem. 2019;26(17):3009–3025. doi:10.2174/0929867324666170804143706
   PubMed Web of Science ®Google Scholar
• Minn AJ, Wherry EJ. Combination Cancer Therapies with Immune Checkpoint Blockade: convergence on Interferon Signaling. Cell. 2016;165(2):272–275. doi:10.1016/j.cell.2016.03.031
   PubMed Web of Science ®Google Scholar
• Wei SC, Duffy CR, Allison JP. Fundamental Mechanisms of Immune Checkpoint Blockade Therapy. Cancer Discov. 2018;8(9):1069–1086. doi:10.1158/2159-8290.CD-18-0367
   PubMed Web of Science ®Google Scholar
• Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359(6382):1350–1355. doi:10.1126/science.aar4060
   PubMed Web of Science ®Google Scholar
• Benci JL, Johnson LR, Choa R, et al. Opposing functions of interferon coordinate adaptive and innate immune responses to cancer immune checkpoint blockade. Cell. 2019;178(4):933–48 e14. doi:10.1016/j.cell.2019.07.019
   PubMed Web of Science ®Google Scholar
• Parkes EE, Walker SM, Taggart LE, et al. Activation of STING-dependent innate immune signaling by s-phase-specific dna damage in breast cancer. J Natl Cancer Inst. 2017;109:1. doi:10.1093/jnci/djw199
   Google Scholar
• Wang H, Hu S, Chen X, et al. cGAS is essential for the antitumor effect of immune checkpoint blockade. Proc Natl Acad Sci U S A. 2017;114(7):1637–1642. doi:10.1073/pnas.1621363114
   PubMed Web of Science ®Google Scholar
• Wilson DR, Sen R, Sunshine JC, et al. Biodegradable STING agonist nanoparticles for enhanced cancer immunotherapy. Nanomedicine. 2018;14(2):237–246. doi:10.1016/j.nano.2017.10.013
   PubMed Web of Science ®Google Scholar
• Ma S, Li X, Wang X, et al. Current Progress in CAR-T Cell Therapy for Solid Tumors. Int J Biol Sci. 2019;15(12):2548–2560. doi:10.7150/ijbs.34213
   PubMed Web of Science ®Google Scholar
• Majzner RG, Mackall CL. Tumor Antigen Escape from CAR T-cell Therapy. Cancer Discov. 2018;8(10):1219–1226. doi:10.1158/2159-8290.CD-18-0442
   PubMed Web of Science ®Google Scholar
• Wei J, Han X, Bo J, et al. Target selection for CAR-T therapy. J Hematol Oncol. 2019;12(1):62. doi:10.1186/s13045-019-0758-x
   PubMedGoogle Scholar
• Minn I, Rowe SP, Pomper MG. Enhancing CAR T-cell therapy through cellular imaging and radiotherapy. Lancet Oncol. 2019;20(8):e443–e51. doi:10.1016/S1470-2045(19)30461-9
   PubMed Web of Science ®Google Scholar
• Wang Z, Wu Z, Liu Y, et al. New development in CAR-T cell therapy. J Hematol Oncol. 2017;10(1):53. doi:10.1186/s13045-017-0423-1
   PubMedGoogle Scholar
• Smith TT, Moffett HF, Stephan SB, et al. Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors. J Clin Invest. 2017;127(6):2176–2191. doi:10.1172/JCI87624
   PubMed Web of Science ®Google Scholar