Abstract
Over the past decade, it has become clear that the stimulator of interferon genes (STING) pathway is critical for a variety of immune responses. This endoplasmic reticulum-anchored adaptor protein has regulatory functions in host immunity across a spectrum of conditions, including infectious diseases, autoimmunity, neurobiology and cancer. In this Review, we outline the central importance of STING in immunological processes driven by expression of type I and III interferons, as well as inflammatory cytokines, and we look at therapeutic options for targeting STING. We also examine evidence that challenges the prevailing notion that STING activation is predominantly beneficial in combating cancer. Further exploration is imperative to discern whether STING activation in the tumor microenvironment confers true benefits or has detrimental effects. Research in this field is at a crossroads, as a clearer understanding of the nuanced functions of STING activation in cancer is required for the development of next-generation therapies.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Zhong, B. et al. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29, 538–550 (2008).
Jin, L. et al. MPYS, a novel membrane tetraspanner, is associated with major histocompatibility complex class II and mediates transduction of apoptotic signals. Mol. Cell. Biol. 28, 5014–5026 (2008).
Ishikawa, H. & Barber, G. N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008).
Sun, W. et al. ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization. Proc. Natl Acad. Sci. USA 106, 8653–8658 (2009).
Ishikawa, H., Ma, Z. & Barber, G. N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792 (2009).
Li, X. D. et al. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 341, 1390–1394 (2013).
Civril, F. et al. Structural mechanism of cytosolic DNA sensing by cGAS. Nature 498, 332–337 (2013).
Burdette, D. L. et al. STING is a direct innate immune sensor of cyclic di-GMP. Nature 478, 515–518 (2011).
Woodward, J. J., Iavarone, A. T. & Portnoy, D. A. c-di-AMP secreted by intracellular Listeria monocytogenes activates a host type I interferon response. Science 328, 1703–1705 (2010).
Zhang, X., Bai, X. C. & Chen, Z. J. Structures and mechanisms in the cGAS–STING innate immunity pathway. Immunity 53, 43–53 (2020).
Hopfner, K. P. & Hornung, V. Molecular mechanisms and cellular functions of cGAS–STING signalling. Nat. Rev. Mol. Cell Biol. 21, 501–521 (2020).
Motwani, M., Pesiridis, S. & Fitzgerald, K. A. DNA sensing by the cGAS–STING pathway in health and disease. Nat. Rev. Genet. 20, 657–674 (2019).
Jeltema, D., Abbott, K. & Yan, N. STING trafficking as a new dimension of immune signaling. J. Exp. Med. 220, e20220990 (2023).
Volkman, H. E., Cambier, S., Gray, E. E. & Stetson, D. B. Tight nuclear tethering of cGAS is essential for preventing autoreactivity. Elife 8, e47491 (2019).
Zhao, B. et al. The molecular basis of tight nuclear tethering and inactivation of cGAS. Nature 587, 673–677 (2020).
Li, T. et al. Phosphorylation and chromatin tethering prevent cGAS activation during mitosis. Science 371, eabc5386 (2021).
Gao, P. et al. Structure-function analysis of STING activation by c[G(2′,5′)pA(3′,5′)p] and targeting by antiviral DMXAA. Cell 154, 748–762 (2013).
Zhang, C. et al. Structural basis of STING binding with and phosphorylation by TBK1. Nature 567, 394–398 (2019).
Yum, S., Li, M., Fang, Y. & Chen, Z. J. TBK1 recruitment to STING activates both IRF3 and NF-κB that mediate immune defense against tumors and viral infections. Proc. Natl Acad. Sci. USA 118, e2100225118 (2021).
Tanaka, Y. & Chen, Z. J. STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Sci. Signal. 5, ra20 (2012).
Balka, K. R. et al. TBK1 and IKKε act redundantly to mediate STING-Induced NF-κB responses in myeloid cells. Cell Rep. 31, 107492 (2020).
Hong, C. et al. cGAS–STING drives the IL-6-dependent survival of chromosomally instable cancers. Nature 607, 366–373 (2022).
Humphries, F. et al. Targeting STING oligomerization with small-molecule inhibitors. Proc. Natl Acad. Sci. USA 120, e2305420120 (2023).
Ergun, S. L., Fernandez, D., Weiss, T. M. & Li, L. STING polymer structure reveals mechanisms for activation, hyperactivation, and inhibition. Cell 178, 290–301 (2019).
Mehta, A. et al. Human induced pluripotent stem cells generated from STING-associated vasculopathy with onset in infancy (SAVI) patients with a heterozygous mutation in the STING gene. Stem Cell Res. 65, 102974 (2022).
Fremond, M. L. et al. Overview of STING-associated vasculopathy with onset in infancy (SAVI) among 21 patients. J. Allergy Clin. Immunol. Pract. 9, 803–818 (2021).
Delafontaine, S. et al. Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome. J. Clin. Invest. 134, e163604 (2024).
Steiner, A. et al. Deficiency in coatomer complex I causes aberrant activation of STING signalling. Nat. Commun. 13, 2321 (2022).
Mukai, K. et al. Homeostatic regulation of STING by retrograde membrane traffic to the ER. Nat. Commun. 12, 61 (2021).
Gentili, M. et al. ESCRT-dependent STING degradation inhibits steady-state and cGAMP-induced signalling. Nat. Commun. 14, 611 (2023).
Balka, K. R. et al. Termination of STING responses is mediated via ESCRT-dependent degradation. EMBO J. 42, e112712 (2023).
Liu, Y. et al. Clathrin-associated AP-1 controls termination of STING signalling. Nature 610, 761–767 (2022).
Wan, W. et al. STING directly recruits WIPI2 for autophagosome formation during STING-induced autophagy. EMBO J. 42, e112387 (2023).
Gui, X. et al. Autophagy induction via STING trafficking is a primordial function of the cGAS pathway. Nature 567, 262–266 (2019).
Kuchitsu, Y. et al. STING signalling is terminated through ESCRT-dependent microautophagy of vesicles originating from recycling endosomes. Nat. Cell Biol. 25, 453–466 (2023).
Ablasser, A. et al. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature 503, 530–534 (2013).
Pepin, G. et al. Connexin-dependent transfer of cGAMP to phagocytes modulates antiviral responses. mBio 11, e03187–19 (2020).
Blest, H. T. W. & Chauveau, L. cGAMP the travelling messenger. Front. Immunol. 14, 1150705 (2023).
Wu, J., Dobbs, N., Yang, K. & Yan, N. Interferon-independent activities of mammalian STING mediate antiviral response and tumor immune evasion. Immunity 53, 115–126 (2020).
Dunphy, G. et al. Non-canonical activation of the DNA sensing adaptor STING by ATM and IFI16 mediates NF-κB signaling after nuclear DNA damage. Mol. Cell 71, 745–760 (2018).
Al-Asmari, S. S. et al. Pharmacological targeting of STING-dependent IL-6 production in cancer cells. Front. Cell Dev. Biol. 9, 709618 (2021).
Meibers, H. E. et al. Effector memory T cells induce innate inflammation by triggering DNA damage and a non-canonical STING pathway in dendritic cells. Cell Rep. 42, 113180 (2023).
Jackson, S. P. The DNA-damage response: new molecular insights and new approaches to cancer therapy. Biochem. Soc. Trans. 37, 483–494 (2009).
Harding, S. M. et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548, 466–470 (2017).
Ghosh, M., Saha, S., Li, J., Montrose, D. C. & Martinez, L. A. p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression. Mol. Cell 83, 266–280 (2023).
Ghosh, M. et al. Mutant p53 suppresses innate immune signaling to promote tumorigenesis. Cancer Cell 39, 494–508 (2021).
Bakhoum, S. F. & Cantley, L. C. The multifaceted role of chromosomal instability in cancer and its microenvironment. Cell 174, 1347–1360 (2018).
Fenech, M. et al. Molecular mechanisms of micronucleus, nucleoplasmic bridge and nuclear bud formation in mammalian and human cells. Mutagenesis 26, 125–132 (2011).
Bakhoum, S. F. et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 553, 467–472 (2018).
Hatch, E. M., Fischer, A. H., Deerinck, T. J. & Hetzer, M. W. Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell 154, 47–60 (2013).
Leuzzi, G. et al. SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion. Cell 187, 861–881 (2024).
Li, C. et al. Targeting MUS81 promotes the anticancer effect of WEE1 inhibitor and immune checkpoint blocking combination therapy via activating cGAS/STING signaling in gastric cancer cells. J. Exp. Clin. Cancer Res. 40, 315 (2021).
Wörmann, S. M. et al. APOBEC3A drives deaminase domain-independent chromosomal instability to promote pancreatic cancer metastasis. Nat. Cancer 2, 1338–1356 (2021).
Teo, Z. L. et al. Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer. NPJ Breast Cancer 9, 68 (2023).
von Loga, K. et al. Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer. Nat. Commun. 11, 139 (2020).
Guan, J. et al. MLH1 deficiency-triggered DNA hyperexcision by exonuclease 1 activates the cGAS–STING pathway. Cancer Cell 39, 109–121 (2021).
Vornholz, L. et al. Synthetic enforcement of STING signaling in cancer cells appropriates the immune microenvironment for checkpoint inhibitor therapy. Sci. Adv. 9, eadd8564 (2023).
Dilley, R. L. & Greenberg, R. A. ALTernative telomere maintenance and cancer. Trends Cancer 1, 145–156 (2015).
Chen, Y.-A. et al. Extrachromosomal telomere repeat DNA is linked to ALT development via cGAS–STING DNA sensing pathway. Nat. Struct. Mol. Biol. 24, 1124–1131 (2017).
Cho, M.-G. et al. MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis. Nature 625, 585–592 (2024).
Bian, L., Meng, Y., Zhang, M. & Li, D. MRE11–RAD50–NBS1 complex alterations and DNA damage response: implications for cancer treatment. Mol. Cancer 18, 169 (2019).
Liu, H. et al. Nuclear cGAS suppresses DNA repair and promotes tumorigenesis. Nature 563, 131–136 (2018).
Xu, P. et al. The CRL5-SPSB3 ubiquitin ligase targets nuclear cGAS for degradation. Nature 627, 873–879 (2024).
Roberts, Z. J., Ching, L. M. & Vogel, S. N. IFN-beta-dependent inhibition of tumor growth by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA). J. Interferon Cytokine Res. 28, 133–139 (2008).
Downey, C. M., Aghaei, M., Schwendener, R. A. & Jirik, F. R. DMXAA causes tumor site-specific vascular disruption in murine non-small cell lung cancer, and like the endogenous non-canonical cyclic dinucleotide STING agonist, 2'3'-cGAMP, induces M2 macrophage repolarization. PLoS ONE 9, e99988 (2014).
Corrales, L. et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 11, 1018–1030 (2015).
Conlon, J. et al. Mouse, but not human STING, binds and signals in response to the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid. J. Immunol. 190, 5216–5225 (2013).
Temizoz, B. et al. 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a partial STING agonist, competes for human STING activation. Front. Immunol. 15, 1353336 (2024).
Deng, L. et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41, 843–852 (2014).
Woo, S. R. et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41, 830–842 (2014).
Wang, J., Meng, F. & Yeo, Y. Delivery of STING agonists for cancer immunotherapy. Curr. Opin. Biotechnol. 87, 103105 (2024).
Jneid, B. et al. Selective STING stimulation in dendritic cells primes antitumor T cell responses. Sci. Immunol. 8, eabn6612 (2023).
Spranger, S., Dai, D., Horton, B. & Gajewski, T. F. Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 31, 711–723 (2017).
Wang, J. et al. STING licensing of type I dendritic cells potentiates antitumor immunity. Sci. Immunol. https://doi.org/10.1126/sciimmunol.adj3945 (2024).
Demaria, O. et al. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc. Natl Acad. Sci. USA 112, 15408–15413 (2015).
Benoit-Lizon, I. et al. CD4 T cell-intrinsic STING signaling controls the differentiation and effector functions of TH1 and TH9 cells. J. Immunother. Cancer 10, e003459 (2022).
Wu, J. et al. STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death. J. Exp. Med. 216, 867–883 (2019).
Kabelitz, D. et al. Signal strength of STING activation determines cytokine plasticity and cell death in human monocytes. Sci. Rep. 12, 17827 (2022).
Gaidt, M. M. et al. The DNA inflammasome in human myeloid cells is initiated by a STING-cell death program upstream of NLRP3. Cell 171, 1110–1124 (2017).
Long, J. et al. Notch signaling protects CD4 T cells from STING-mediated apoptosis during acute systemic inflammation. Sci. Adv. 6, eabc5447 (2020).
Quaney, M. J. et al. STING controls T cell memory fitness during infection through T cell-intrinsic and IDO-dependent mechanisms. Proc. Natl Acad. Sci. USA 120, e2205049120 (2023).
Larkin, B. et al. Cutting edge: activation of STING in T cells induces type I IFN responses and cell death. J. Immunol. 199, 397–402 (2017).
Sivick, K. E. et al. Magnitude of therapeutic STING activation determines CD8+ T cell-mediated anti-tumor immunity. Cell Rep. 25, 3074–3085 (2018).
Meric-Bernstam, F. et al. Phase I dose-escalation trial of MIW815 (ADU-S100), an intratumoral STING agonist, in patients with advanced/metastatic solid tumors or lymphomas. Clin. Cancer Res. 28, 677–688 (2022).
Meric-Bernstam, F. et al. Combination of the STING agonist MIW815 (ADU-S100) and PD-1 inhibitor spartalizumab in advanced/metastatic solid tumors or lymphomas: an open-label, multicenter, phase ib study. Clin. Cancer Res. 29, 110–121 (2023).
Hines, J. B., Kacew, A. J. & Sweis, R. F. The development of STING agonists and emerging results as a cancer immunotherapy. Curr. Oncol. Rep. 25, 189–199 (2023).
Pan, B. S. et al. An orally available non-nucleotide STING agonist with antitumor activity. Science 369, eaba6098 (2020).
Chin, E. N. et al. Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic. Science 369, 993–999 (2020).
Zhang, P. et al. STING agonist-loaded, CD47/PD-L1-targeting nanoparticles potentiate antitumor immunity and radiotherapy for glioblastoma. Nat. Commun. 14, 1610 (2023).
Nakamura, T. et al. STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation. J. Immunother. Cancer 9, e002852 (2021).
Amouzegar, A., Chelvanambi, M., Filderman, J. N., Storkus, W. J. & Luke, J. J. STING agonists as cancer therapeutics. Cancers 13, 2695 (2021).
Soomer-James, J., Damelin, M. & Malli, N. XMT-2056, a HER2-targeted STING agonist antibody–drug conjugate, exhibits ADCC function that synergizes with STING pathway activation and contributes to anti-tumor responses. Cancer Res. 83, 4423 (2023).
Duvall, J. R. et al. XMT-2056, a HER2-targeted Immunosynthen STING-agonist antibody-drug conjugate, binds a novel epitope of HER2 and shows increased anti-tumor activity in combination with trastuzumab and pertuzumab. Cancer Res. 82, 3503 (2022).
Wang, X. et al. The role of CXCR3 and its ligands in cancer. Front. Oncol. 12, 1022688 (2022).
Hoch, T. et al. Multiplexed imaging mass cytometry of the chemokine milieus in melanoma characterizes features of the response to immunotherapy. Sci. Immunol. 7, eabk1692 (2022).
Ribas, A. et al. Overcoming PD-1 blockade resistance with CpG-A toll-like receptor 9 agonist vidutolimod in patients with metastatic melanoma. Cancer Discov. 11, 2998–3007 (2021).
Bill, R. et al. CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers. Science 381, 515–524 (2023).
Biskup, E. et al. Photochemotherapy induces interferon type III expression via STING pathway. Cells 9, 2452 (2020).
Pang, E. S. et al. Discordance in STING-induced activation and cell death between mouse and human dendritic cell populations. Front. Immunol. 13, 794776 (2022).
Sui, H. et al. STING is an essential mediator of the Ku70-mediated production of IFN-λ1 in response to exogenous DNA. Sci. Signal. 10, eaah5054 (2017).
Lazear, H. M., Nice, T. J. & Diamond, M. S. Interferon-lambda: immune functions at barrier surfaces and beyond. Immunity 43, 15–28 (2015).
Hemann, E. A. et al. Interferon-lambda modulates dendritic cells to facilitate T cell immunity during infection with influenza A virus. Nat. Immunol. 20, 1035–1045 (2019).
Read, S. A. et al. Macrophage coordination of the interferon lambda immune response. Front. Immunol. 10, 2674 (2019).
Mennechet, F. J. & Uze, G. Interferon-lambda-treated dendritic cells specifically induce proliferation of FOXP3-expressing suppressor T cells. Blood 107, 4417–4423 (2006).
Galani, I. E. et al. Interferon-lambda mediates non-redundant front-line antiviral protection against influenza virus infection without compromising host fitness. Immunity 46, 875–890 (2017).
Hubert, M. et al. IFN-III is selectively produced by cDC1 and predicts good clinical outcome in breast cancer. Sci. Immunol. 5, eaav3942 (2020).
Reis, G. et al. Early treatment with pegylated interferon lambda for COVID-19. N. Engl. J. Med. 388, 518–528 (2023).
Loo, T. M., Miyata, K., Tanaka, Y. & Takahashi, A. Cellular senescence and senescence-associated secretory phenotype via the cGAS–STING signaling pathway in cancer. Cancer Sci. 111, 304–311 (2020).
Gluck, S. et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol. 19, 1061–1070 (2017).
Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402–406 (2017).
Victorelli, S. et al. Apoptotic stress causes mtDNA release during senescence and drives the SASP. Nature 622, 627–636 (2023).
Kuang, F., Liu, J., Li, C., Kang, R. & Tang, D. Cathepsin B is a mediator of organelle-specific initiation of ferroptosis. Biochem. Biophys. Res. Commun. 533, 1464–1469 (2020).
Gao, Y. et al. Intercellular transfer of activated STING triggered by RAB22A-mediated non-canonical autophagy promotes antitumor immunity. Cell Res. 32, 1086–1104 (2022).
Zhang, L. et al. STING is a cell-intrinsic metabolic checkpoint restricting aerobic glycolysis by targeting HK2. Nat. Cell Biol. 25, 1208–1222 (2023).
Hayman, T. J. et al. STING enhances cell death through regulation of reactive oxygen species and DNA damage. Nat. Commun. 12, 2327 (2021).
Yamashiro, L. H. et al. Interferon-independent STING signaling promotes resistance to HSV-1 in vivo. Nat. Commun. 11, 3382 (2020).
Li, S. et al. STING-induced regulatory B cells compromise NK function in cancer immunity. Nature 610, 373–380 (2022).
Kim, J. et al. Downstream STING pathways IRF3 and NF-κB differentially regulate CCL22 in response to cytosolic dsDNA. Cancer Gene Ther. 31, 28–42 (2024).
Orange, S. T., Leslie, J., Ross, M., Mann, D. A. & Wackerhage, H. The exercise IL-6 enigma in cancer. Trends Endocrinol. Metab. 34, 749–763 (2023).
Briukhovetska, D. et al. Interleukins in cancer: from biology to therapy. Nat. Rev. Cancer 21, 481–499 (2021).
Mauer, J., Denson, J. L. & Bruning, J. C. Versatile functions for IL-6 in metabolism and cancer. Trends Immunol. 36, 92–101 (2015).
Carozza, J. A. et al. Extracellular cGAMP is a cancer cell-produced immunotransmitter involved in radiation-induced anti-cancer immunity. Nat. Cancer 1, 184–196 (2020).
Maltbaek, J. H., Cambier, S., Snyder, J. M. & Stetson, D. B. ABCC1 transporter exports the immunostimulatory cyclic dinucleotide cGAMP. Immunity 55, 1799–1812 (2022).
Kato, K. et al. Structural insights into cGAMP degradation by ecto-nucleotide pyrophosphatase phosphodiesterase 1. Nat. Commun. 9, 4424 (2018).
Li, L. et al. Hydrolysis of 2'3'-cGAMP by ENPP1 and design of nonhydrolyzable analogs. Nat. Chem. Biol. 10, 1043–1048 (2014).
Carozza, J. A. et al. Structure-aided development of small-molecule inhibitors of ENPP1, the extracellular phosphodiesterase of the immunotransmitter cGAMP. Cell Chem. Biol. 27, 1347–1358 (2020).
Concepcion, A. R. et al. The volume-regulated anion channel LRRC8C suppresses T cell function by regulating cyclic dinucleotide transport and STING-p53 signaling. Nat. Immunol. 23, 287–302 (2022).
Zhou, C. et al. Transfer of cGAMP into bystander cells via LRRC8 Volume-regulated anion channels augments STING-mediated interferon responses and anti-viral immunity. Immunity 52, 767–781 (2020).
Zhou, Y. et al. Blockade of the phagocytic receptor MerTK on tumor-associated macrophages enhances P2X7R-dependent STING activation by tumor-derived cGAMP. Immunity 52, 357–373 (2020).
Ritchie, C., Cordova, A. F., Hess, G. T., Bassik, M. C. & Li, L. SLC19A1 is an importer of the immunotransmitter cGAMP. Mol. Cell 75, 372–381 (2019).
Luteijn, R. D. et al. SLC19A1 transports immunoreactive cyclic dinucleotides. Nature 573, 434–438 (2019).
Cordova, A. F., Ritchie, C., Bohnert, V. & Li, L. Human SLC46A2 is the dominant cGAMP importer in extracellular cGAMP-sensing macrophages and monocytes. ACS Cent. Sci. 7, 1073–1088 (2021).
Carozza, J. A. et al. ENPP1’s regulation of extracellular cGAMP is a ubiquitous mechanism of attenuating STING signaling. Proc. Natl Acad. Sci. USA 119, e2119189119 (2022).
Li, J. et al. Metastasis and immune evasion from extracellular cGAMP hydrolysis. Cancer Discov. 11, 1212–1227 (2021).
Gangar, M. et al. Design, synthesis and biological evaluation studies of novel small molecule ENPP1 inhibitors for cancer immunotherapy. Bioorg. Chem. 119, 105549 (2022).
Solomon, P. E. et al. Discovery of VH domains that allosterically inhibit ENPP1. Nat. Chem. Biol. 20, 30–41 (2024).
Groelly, F. J., Fawkes, M., Dagg, R. A., Blackford, A. N. & Tarsounas, M. Targeting DNA damage response pathways in cancer. Nat. Rev. Cancer 23, 78–94 (2023).
Nakajima, S. et al. Radiation-induced remodeling of the tumor microenvironment through tumor cell-intrinsic expression of cGAS–STING in esophageal squamous cell carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 115, 957–971 (2023).
Lv, J. et al. The tumor immune microenvironment of nasopharyngeal carcinoma after gemcitabine plus cisplatin treatment. Nat. Med. 29, 1424–1436 (2023).
Ding, L. et al. PARP inhibition elicits STING-dependent antitumor immunity in Brca1-deficient ovarian cancer. Cell Rep. 25, 2972–2980 (2018).
Ding, L. et al. STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer. J. Immunother. Cancer 11, e005627 (2023).
Wang, Q. et al. STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer. Nat. Commun. 13, 3022 (2022).
Zhu, Q. et al. Novel dual inhibitors of PARP and HDAC induce intratumoral STING-mediated antitumor immunity in triple-negative breast cancer. Cell Death Dis. 15, 10 (2024).
Ma, Z. et al. AhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer. Nat. Commun. 14, 5415 (2023).
Opitz, C. A., Holfelder, P., Prentzell, M. T. & Trump, S. The complex biology of aryl hydrocarbon receptor activation in cancer and beyond. Biochem. Pharmacol. 216, 115798 (2023).
Vanpouille-Box, C. et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 8, 15618 (2017).
Salojin, C. et al. The first-in-class small molecule TREX1 inhibitor CPI-381 demonstrates type I IFN induction and sensitization of tumors to immune checkpoint blockade. J. Immunother. Cancer 9, A800 (2021).
Chen, V. et al. Generation of novel potent human TREX1 inhibitors facilitated by crystallography. Cancer Res. 83, 1636 (2023).
Sen, T. et al. Targeting DNA damage response promotes antitumor immunity through STING-mediated T-cell activation in small cell lung cancer. Cancer Discov. 9, 646–661 (2019).
Du, S. S. et al. Radiation therapy promotes hepatocellular carcinoma immune cloaking via PD-L1 upregulation induced by cGAS–STING activation. Int. J. Radiat. Oncol. Biol. Phys. 112, 1243–1255 (2022).
Luo, W. et al. Critical role of the cGAS–STING pathway in doxorubicin-induced cardiotoxicity. Circ. Res. 132, e223–e242 (2023).
Ni, H. et al. T cell-intrinsic STING signaling promotes regulatory T cell induction and immunosuppression by upregulating FOXP3 transcription in cervical cancer. J. Immunother. Cancer 10, e005151 (2022).
Couillin, I. & Riteau, N. STING signaling and sterile inflammation. Front. Immunol. 12, 753789 (2021).
Xia, T., Konno, H., Ahn, J. & Barber, G. N. Deregulation of STING signaling in colorectal carcinoma constrains DNA damage responses and correlates with tumorigenesis. Cell Rep. 14, 282–297 (2016).
Konno, H. et al. Suppression of STING signaling through epigenetic silencing and missense mutation impedes DNA damage mediated cytokine production. Oncogene 37, 2037–2051 (2018).
Falahat, R. et al. Epigenetic state determines the in vivo efficacy of STING agonist therapy. Nat. Commun. 14, 1573 (2023).
Lai, J. et al. Zebularine elevates STING expression and enhances cGAMP cancer immunotherapy in mice. Mol. Ther. 29, 1758–1771 (2021).
Wu, L. et al. KDM5 histone demethylases repress immune response via suppression of STING. PLoS Biol. 16, e2006134 (2018).
Kottakis, F. et al. LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature 539, 390–395 (2016).
Lee, K. M. et al. Epigenetic repression of STING by MYC promotes immune evasion and resistance to immune checkpoint inhibitors in triple-negative breast cancer. Cancer Immunol. Res. 10, 829–843 (2022).
Liu, X. & Winey, M. The MPS1 family of protein kinases. Annu. Rev. Biochem. 81, 561–585 (2012).
Hu, X. et al. TTK inhibition activates STING signal and promotes anti-PD1 immunotherapy in breast cancer. Biochem. Biophys. Res. Commun. 694, 149388 (2024).
Kitajima, S. et al. MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer. Cancer Cell 40, 1128–1144 (2022).
Kobelt, D. et al. Pro-inflammatory TNF-α and IFN-γ promote tumor growth and metastasis via induction of MACC1. Front. Immunol. 11, 980 (2020).
Filderman, J. N. et al. Antagonism of regulatory ISGs enhances the anti-melanoma efficacy of STING agonists. Front. Immunol. 15, 1334769 (2024).
Lee, S. E. et al. Improvement of STING-mediated cancer immunotherapy using immune checkpoint inhibitors as a game-changer. Cancer Immunol. Immunother. 71, 3029–3042 (2022).
Chen, W. et al. Chronic type I interferon signaling promotes lipid-peroxidation-driven terminal CD8+ T cell exhaustion and curtails anti-PD-1 efficacy. Cell Rep. 41, 111647 (2022).
Ahn, J. et al. Inflammation-driven carcinogenesis is mediated through STING. Nat. Commun. 5, 5166 (2014).
Bakhoum, M. F. et al. Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression. Nat. Commun. 12, 5402 (2021).
Zhao, M. et al. Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response. Nat. Commun. 15, 180 (2024).
Li, J. et al. Non-cell-autonomous cancer progression from chromosomal instability. Nature 620, 1080–1088 (2023).
Haag, S. M. et al. Targeting STING with covalent small-molecule inhibitors. Nature 559, 269–273 (2018).
Nakamura, M. et al. Development of STING degrader with double covalent ligands. Bioorg. Med. Chem. Lett. 102, 129677 (2024).
Zhu, Z. et al. Development of VHL-recruiting STING PROTACs that suppress innate immunity. Cell. Mol. Life Sci. 80, 149 (2023).
Liu, J. et al. Novel CRBN-recruiting proteolysis-targeting chimeras as degraders of stimulator of interferon genes with in vivo anti-inflammatory efficacy. J. Med. Chem. 65, 6593–6611 (2022).
Birkbak, N. J. et al. Paradoxical relationship between chromosomal instability and survival outcome in cancer. Cancer Res. 71, 3447–3452 (2011).
Acknowledgements
We are supported by funding from the Lundbeck foundation (grant no. R238-2016-2708), the Novo Nordisk Foundation Distinguished Innovator (grant no. NNF20OC0062825) and the Danish Cancer Society (grant no. R231-A14090). We are grateful for the support by R. O. Bak and A. Etzerodt providing valuable input and discussion of subjects entailed in the Review. We acknowledge the existence of several relevant research papers, which hold valuable insights and contributions to the field, that we were not able to incorporate in this Review.
Author information
Authors and Affiliations
Contributions
M.R.J. developed the concept of the manuscript. K.R.B.L. and E.L.L. contributed to the drafting of the manuscript and generating figures. All authors edited and approved the final version.
Corresponding author
Ethics declarations
Competing interests
M.R.J. is scientific cofounder and board member of STipe Therapeutics and Unikum Therapeutics. K.R.B.L. and E.L.L. declare no competing interests.
Peer review
Peer review information
Nature Immunology thanks Michael Gantier, Nan Yan, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Nick Bernard, in collaboration with the Nature Immunology team.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Lanng, K.R.B., Lauridsen, E.L. & Jakobsen, M.R. The balance of STING signaling orchestrates immunity in cancer. Nat Immunol 25, 1144–1157 (2024). https://doi.org/10.1038/s41590-024-01872-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41590-024-01872-3
