The emerging role of STING-dependent signaling on cell death

  • Feng Sun
  • Zhijian Liu
  • Zhengyang Yang
  • Song LiuEmail author
  • Wenxian GuanEmail author


STING is a newly identified adaptor protein for sensing cytosolic nucleic acid. It is well established that STING plays a crucial role in innate immune response via inducing production of type I IFN. Emerging evidence suggests that the activation of STING-dependent signaling is also implicated in the process of cell death, such as apoptosis, pyroptosis, necroptosis, and autophagy. Of note, the pro-death outcome is even predominant in certain cell types, like lymphocytes, myeloid cells, and hepatocytes. Given that STING agonists are being tested for enhancing antitumor immune responses, it is necessary to fully understand the outcome of STING activation. The anti-microorganism response mediated by STING has been well described; therefore, we focus on the role of STING-dependent signaling on cell death in this review.


STING IRF3 Apoptosis Pyroptosis Necroptosis Autophagy 


Author contributions’ statement

F.S. and S.L. wrote the manuscript. Z.L. collected the references and revised the manuscript. Z.Y. helped in language editing. W.G. supervised the review.

Funding information

This study is supported by the National Natural Science Foundation of China (81602103), Natural Science Foundation of Jiangsu Province (BK20160114), Distinguished Young Scholar Project of Medical Science and Technology Development Foundation of Nanjing Department of Health (JQX17005), Key Project of Medical Science and Technology Development Foundation of Nanjing Department of Health (YKK16114), Medical Research Program of Jiangsu Provincial Commission of Health and Family Planning (Q2017007), and Wu Jieping Medical Foundation (320.2710.1817).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008;455(7213):674–U74. Scholar
  2. 2.
    Ng KW, Marshall EA, Bell JC, Lam WL. cGAS–STING and cancer: dichotomous roles in tumor immunity and development. Trends Immunol. 2017.Google Scholar
  3. 3.
    Barber GN. STING: infection, inflammation and cancer. Nat Rev Immunol. 2015;15(12):760–70.CrossRefGoogle Scholar
  4. 4.
    Ahn J, Barber GN. Self-DNA, STING-dependent signaling and the origins of autoinflammatory disease. Curr Opin Immunol. 2014;31:121–6. Scholar
  5. 5.
    West AP, Khoury-Hanold W, Staron M, Tal MC, Pineda CM, Lang SM, et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature. 2015;520(7548):553–+. Scholar
  6. 6.
    Sun L, Wu J, Du F, Chen X, Chen ZJ. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 2013;339(6121):786–91. Scholar
  7. 7.
    Cai X, Chiu Y-H, Chen ZJ. The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. Mol Cell. 2014;54(2):289–96. Scholar
  8. 8.
    Burdette DL, Monroe KM, Sotelo-Troha K, Iwig JS, Eckert B, Hyodo M, et al. STING is a direct innate immune sensor of cyclic di-GMP. Nature. 2011;478(7370):515–U111. Scholar
  9. 9.
    Woodward JJ, Iavarone AT, Portnoy DA. C-di-AMP secreted by intracellular listeria monocytogenes activates a host type I interferon response. Science. 2010;328(5986):1703–5. Scholar
  10. 10.
    Corrales L, Glickman LH, McWhirter SM, Kanne DB, Sivick KE, Katibah GE, et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 2015;11(7):1018–30. Scholar
  11. 11.
    Woo S-R, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung MYK, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014;41(5):830–42. Scholar
  12. 12.
    Gao P, Zillinger T, Wang W, Ascano M, Dai P, Hartmann G, et al. Binding-pocket and lid-region substitutions render human STING sensitive to the species-specific drug DMXAA. Cell Rep. 2014;8(6):1668–76. Scholar
  13. 13.
    Luo M, Wang H, Wang Z, Cai H, Lu Z, Li Y, et al. A STING-activating nanovaccine for cancer immunotherapy. Nat Nanotechnol. 2017;12(7):648–+. Scholar
  14. 14.
    Fu J, Kanne DB, Leong M, Glickman LH, McWhirter SM, Lemmens E, et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci Transl Med. 2015;7(283):283ra52. Scholar
  15. 15.
    Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014;41(5):843–52. Scholar
  16. 16.
    Corrales L, McWhirter SM, Dubensky TW Jr, Gajewski TF. The host STING pathway at the interface of cancer and immunity. J Clin Investig. 2016;126(7):2404–11. Scholar
  17. 17.
    Cheng N, Watkins-Schulz R, Junkins RD, David CN, Johnson BM, Montgomery SA, et al. A nanoparticle-incorporated STING activator enhances antitumor immunity in PD-L1-insensitive models of triple-negative breast cancer. JCI Insight. 2018;3(22).
  18. 18.
    Wilson DR, Sen R, Sunshine JC, Pardoll DM, Green JJ, Kim YJ. Biodegradable STING agonist nanoparticles for enhanced cancer immunotherapy. Nanomedicine. 2018;14(2):237–46. Scholar
  19. 19.
    Hanson MC, Crespo MP, Abraham W, Moynihan KD, Szeto GL, Chen SH, et al. Nanoparticulate STING agonists are potent lymph node-targeted vaccine adjuvants. J Clin Invest. 2015;125(6):2532–46. Scholar
  20. 20.
    Aroh C, Wang Z, Dobbs N, Luo M, Chen Z, Gao J, et al. Innate immune activation by cGMP-AMP nanoparticles leads to potent and long-acting antiretroviral response against HIV-1. J Immunol. 2017;199(11):3840–8. Scholar
  21. 21.
    An M, Yu C, Xi J, Reyes J, Mao G, Wei WZ, 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):9311–9. Scholar
  22. 22.
    Ramanjulu JM, Pesiridis GS, Yang J, Concha N, Singhaus R, Zhang SY, et al. Design of amidobenzimidazole STING receptor agonists with systemic activity. Nature. 2018;564(7736):439–43. Scholar
  23. 23.
    Konno H, Konno K, Barber GN. Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell. 2013;155(3):688–98. Scholar
  24. 24.
    Gulen MF, Koch U, Haag SM, Schuler F, Apetoh L, Villunger A, et al. Signalling strength determines proapoptotic functions of STING. Nat Commun. 2017;8(1):427. Scholar
  25. 25.
    Moretti J, Roy S, Bozec D, Martinez J, Chapman JR, Ueberheide B, et al. STING senses microbial viability to orchestrate stress-mediated autophagy of the endoplasmic reticulum. Cell. 2017;171(4):809–23 e13. Scholar
  26. 26.
    Tang CH, Zundell JA, Ranatunga S, Lin C, Nefedova Y, Del Valle JR, et al. Agonist-mediated activation of STING induces apoptosis in malignant B cells. Cancer Res. 2016;76(8):2137–52. Scholar
  27. 27.
    Sze A, Belgnaoui SM, Olagnier D, Lin R, Hiscott J, van Grevenynghe J. Host restriction factor SAMHD1 limits human T cell leukemia virus type 1 infection of monocytes via STING-mediated apoptosis. Cell Host Microbe. 2013;14(4):422–34. Scholar
  28. 28.
    Cui Y, Zhao D, Sreevatsan S, Liu C, Yang W, Song Z, et al. Mycobacterium bovis induces endoplasmic reticulum stress mediated-apoptosis by activating IRF3 in a murine macrophage cell line. Front Cell Infect Microbiol. 2016;6:182. Scholar
  29. 29.
    Petrasek J, Iracheta-Vellve A, Csak T, Satishchandran A, Kodys K, Kurt-Jones EA, et al. STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease. Proc Natl Acad Sci U S A. 2013;110(41):16544–9. Scholar
  30. 30.
    Iracheta-Vellve A, Petrasek J, Gyongyosi B, Satishchandran A, Lowe P, Kodys K, et al. Endoplasmic reticulum stress-induced hepatocellular death pathways mediate liver injury and fibrosis via stimulator of interferon genes. J Biol Chem. 2016;291(52):26794–805.
  31. 31.
    Qiao JT, Cui C, Qing L, Wang LS, He TY, Yan F, et al. Activation of the STING-IRF3 pathway promotes hepatocyte inflammation, apoptosis and induces metabolic disorders in nonalcoholic fatty liver disease. Metabolism. 2018;81:13–24. Scholar
  32. 32.
    Webster SJ, Brode S, Ellis L, Fitzmaurice TJ, Elder MJ, Gekara NO, et al. Detection of a microbial metabolite by STING regulates inflammasome activation in response to chlamydia trachomatis infection. PLoS Pathog. 2017;13(6):e1006383. Scholar
  33. 33.
    Man SM, Karki R, Malireddi RK, Neale G, Vogel P, Yamamoto M, et al. The transcription factor IRF1 and guanylate-binding proteins target activation of the AIM2 inflammasome by Francisella infection. Nat Immunol. 2015;16(5):467–75. Scholar
  34. 34.
    Gaidt MM, Ebert TS, Chauhan D, Ramshorn K, Pinci F, Zuber S, 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. Scholar
  35. 35.
    Schock SN, Chandra NV, Sun Y, Irie T, Kitagawa Y, Gotoh B, et al. Induction of necroptotic cell death by viral activation of the RIG-I or STING pathway. Cell Death Differ. 2017;24(4):615–25. Scholar
  36. 36.
    Brault M, Olsen TM, Martinez J, Stetson DB, Oberst A. Intracellular nucleic acid sensing triggers necroptosis through synergistic type I IFN and TNF signaling. J Immunol. 2018;200(8):2748–56. Scholar
  37. 37.
    Bhatelia K, Singh K, Prajapati P, Sripada L, Roy M, Singh R. MITA modulated autophagy flux promotes cell death in breast cancer cells. Cell Signal. 2017;35:73–83. Scholar
  38. 38.
    White MJ, McArthur K, Metcalf D, Lane RM, Cambier JC, Herold MJ, et al. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell. 2014;159(7):1549–62. Scholar
  39. 39.
    Rongvaux A, Jackson R, Harman CCD, Li T, West AP, de Zoete MR, et al. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell. 2014;159(7):1563–77. Scholar
  40. 40.
    Larkin B, Ilyukha V, Sorokin M, Buzdin A, Vannier E, Poltorak A. Cutting edge: activation of STING in T cells induces type I IFN responses and cell death. J Immunol. 2017;199(2):397–402. Scholar
  41. 41.
    Divangahi M, Behar SM, Remold H. Dying to live: how the death modality of the infected macrophage modulates immunity to tuberculosis. In: Divangahi M, editor. New Paradigm of Immunity to Tuberculosis. Adv Exp Med Biol, 2013. p. 103–120.Google Scholar
  42. 42.
    Orzalli MH, Kagan JC. Apoptosis and necroptosis as host defense strategies to prevent viral infection. Trends Cell Biol. 2017;27(11):800–9. Scholar
  43. 43.
    Chattopadhyay S, Kuzmanovic T, Zhang Y, Wetzel JL, Sen GC. Ubiquitination of the transcription factor IRF-3 activates RIPA, the apoptotic pathway that protects mice from viral pathogenesis. Immunity. 2016;44(5):1151–61. Scholar
  44. 44.
    McArthur K, Whitehead LW, Heddleston JM, Li L, Padman BS, Oorschot V, et al. BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science. 2018;359(6378):eaao6047. Scholar
  45. 45.
    Jorgensen I, Miao EA. Pyroptotic cell death defends against intracellular pathogens. Immunol Rev. 2015;265(1):130–42. Scholar
  46. 46.
    Corrales L, Woo SR, Williams JB, McWhirter SM, Dubensky TW Jr, Gajewski TF. Antagonism of the STING pathway via activation of the AIM2 inflammasome by intracellular DNA. J Immunol. 2016;196(7):3191–8. Scholar
  47. 47.
    Banerjee I, Behl B, Mendonca M, Shrivastava G, Russo AJ, Menoret A, et al. Gasdermin D restrains type I interferon response to cytosolic DNA by disrupting ionic homeostasis. Immunity. 2018;49(3):413–26 e5. Scholar
  48. 48.
    Chen D, Tong J, Yang L, Wei L, Stolz DB, Yu J, et al. PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors. Proc Natl Acad Sci U S A. 2018;115(15):3930–5. Scholar
  49. 49.
    Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011;147(4):728–41. Scholar
  50. 50.
    Kobayashi S. Choose delicately and reuse adequately: the newly revealed process of autophagy. Biol Pharm Bull. 2015;38(8):1098–103. Scholar
  51. 51.
    Zhang Y, Whaley-Connell AT, Sowers JR, Ren J. Autophagy as an emerging target in cardiorenal metabolic disease: from pathophysiology to management. Pharmacol Ther. 2018;191:1–22. Scholar
  52. 52.
    White E. The role for autophagy in cancer. J Clin Investig. 2015;125(1):42–6. Scholar
  53. 53.
    Efeyan A, Comb WC, Sabatini DM. Nutrient-sensing mechanisms and pathways. Nature. 2015;517(7534):302–10. Scholar
  54. 54.
    Kaur J, Debnath J. Autophagy at the crossroads of catabolism and anabolism. Nat Rev Mol Cell Biol. 2015;16(8):461–72. Scholar
  55. 55.
    Liu Y, Levine B. Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ. 2015;22(3):367–76. Scholar
  56. 56.
    Roos WP, Thomas AD, Kaina B. DNA damage and the balance between survival and death in cancer biology. Nat Rev Cancer. 2016;16(1):20–33. Scholar
  57. 57.
    Liang Q, Seo GJ, Choi YJ, Ge J, Rodgers MA, Shi M, et al. Autophagy side of MB21D1/cGAS DNA sensor. Autophagy. 2014;10(6):1146–7. Scholar
  58. 58.
    Moretti J, Blander JM. Detection of a vita-PAMP STINGs cells into reticulophagy. Autophagy. 2018;14(6):1102–4. Scholar
  59. 59.
    Watson RO, Bell SL, MacDuff DA, Kimmey JM, Diner EJ, Olivas J, et al. The cytosolic sensor cGAS detects mycobacterium tuberculosis DNA to induce type I interferons and activate autophagy. Cell Host Microbe. 2015;17(6):811–9. Scholar
  60. 60.
    Liu Y, Gordesky-Gold B, Leney-Greene M, Weinbren NL, Tudor M, Cherry S. Inflammation-induced, STING-dependent autophagy restricts Zika virus infection in the drosophila brain. Cell Host Microbe. 2018;24(1):57–68 e3. Scholar
  61. 61.
    Liu D, Wu H, Wang C, Li Y, Tian H, Siraj S, et al. STING directly activates autophagy to tune the innate immune response. Cell Death Differ. 2018.

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Gastrointestinal Surgery, Nanjing Drum Tower HospitalNanjing University Medical SchoolNanjingChina

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