Abstracts
While Stimulator-of-interferon genes (STING) is an innate immune adapter cruicial for sensing cytosolic DNA and modulating immune microenvironment, its tumor-promoting role in tumor survival and immune evasion remains largely unknown. Here we reported that renal cancer cells are exceptionally dependent on STING for survival and evading immunosurveillance via suppressing ER stress-mediated pyroptosis. We found that STING is significantly amplified and upregulated in clear cell renal cell carcinoma (ccRCC), and its elevated expression is associated with worse clinical outcomes. Mechanically, STING depletion in RCC cells specifically triggers activation of the PERK/eIF2α/ATF4/CHOP pathway and activates cleavage of Caspase-8, thereby inducing GSDMD-mediated pyroptosis, which is independent of the innate immune pathway of STING. Moreover, animal study revealed that STING depletion promoted infiltration of CD4+ and CD8+ T cells, consequently boosting robust antitumor immunity via pyroptosis-induced inflammation. From the perspective of targeted therapy, we found that Compound SP23, a PROTAC STING degrader, demonstrated comparable efficacy to STING depletion both in vitro and in vivo for treatment of ccRCC. These findings collectively unveiled an unforeseen function of STING in regulating GSDMD-dependent pyroptosis, thus regulating immune response in RCC. Consequently, pharmacological degradation of STING by SP23 may become an attractive strategy for treatment of advanced RCC.
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All datasets and raw data generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.
References
Jonasch E, Walker CL, Rathmell WK. Clear cell renal cell carcinoma ontogeny and mechanisms of lethality. Nat Rev Nephrol. 2021;17:245–61.
Diaz-Montero CM, Rini BI, Finke JH. The immunology of renal cell carcinoma. Nat Rev Nephrol. 2020;16:721–35.
Aggen DH, Drake CG, Rini BI. Targeting PD-1 or PD-L1 in Metastatic Kidney Cancer: Combination Therapy in the First-Line Setting. Clin Cancer Res. 2020;26:2087–95.
Hebert DN, Molinari M. In and out of the ER: protein folding, quality control, degradation, and related human diseases. Physiol Rev. 2007;87:1377–408.
Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol. 2020;21:421–38.
Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334:1081–6.
Braakman I, Bulleid NJ. Protein folding and modification in the mammalian endoplasmic reticulum. Annu Rev Biochem. 2011;80:71–99.
Braakman I, Hebert DN. Protein folding in the endoplasmic reticulum. Cold Spring Harb Perspect Biol. 2013;5:a013201.
Han J, Back SH, Hur J, Lin YH, Gildersleeve R, Shan J, et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol. 2013;15:481–90.
Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 2004;18:3066–77.
King AP, Wilson JJ. Endoplasmic reticulum stress: an arising target for metal-based anticancer agents. Chem Soc Rev. 2020;49:8113–36.
Deng H, Zhou Z, Yang W, Lin LS, Wang S, Niu G, et al. Endoplasmic Reticulum Targeting to Amplify Immunogenic Cell Death for Cancer Immunotherapy. Nano Lett. 2020;20:1928–33.
Li W, Yang J, Luo L, Jiang M, Qin B, Yin H, et al. Targeting photodynamic and photothermal therapy to the endoplasmic reticulum enhances immunogenic cancer cell death. Nat Commun. 2019;10:3349.
Rufo N, Garg AD, Agostinis P. The Unfolded Protein Response in Immunogenic Cell Death and Cancer Immunotherapy. Trends Cancer. 2017;3:643–58.
Liu X, Xia S, Zhang Z, Wu H, Lieberman J. Channelling inflammation: gasdermins in physiology and disease. Nat Rev Drug Discov. 2021;20:384–405.
Broz P, Pelegrin P, Shao F. The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol. 2020;20:143–57.
Lu Y, Xu F, Wang Y, Shi C, Sha Y, He G, et al. Cancer immunogenic cell death via photo-pyroptosis with light-sensitive Indoleamine 2,3-dioxygenase inhibitor conjugate. Biomaterials. 2021;278:121167.
Rosenbaum SR, Wilski NA, Aplin AE. Fueling the Fire: Inflammatory Forms of Cell Death and Implications for Cancer Immunotherapy. Cancer Discov. 2021;11:266–81.
Erkes DA, Cai W, Sanchez IM, Purwin TJ, Rogers C, Field CO, et al. Mutant BRAF and MEK Inhibitors Regulate the Tumor Immune Microenvironment via Pyroptosis. Cancer Discov. 2020;10:254–69.
Wang Q, Wang Y, Ding J, Wang C, Zhou X, Gao W, et al. A bioorthogonal system reveals antitumour immune function of pyroptosis. Nature. 2020;579:421–6.
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;478:515–8.
Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008;455:674–8.
Bhatelia K, Singh A, Tomar D, Singh K, Sripada L, Chagtoo M, 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;1842:144–53.
Xia T, Konno H, Ahn J, Barber GN. Deregulation of STING Signaling in Colorectal Carcinoma Constrains DNA Damage Responses and Correlates With Tumorigenesis. Cell Rep. 2016;14:282–97.
Xia T, Konno H, Barber GN. Recurrent Loss of STING Signaling in Melanoma Correlates with Susceptibility to Viral Oncolysis. Cancer Res. 2016;76:6747–59.
Liang D, Xiao-Feng H, Guan-Jun D, Er-Ling H, Sheng C, Ting-Ting W, 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;1852:2494–503.
Takashima K, Takeda Y, Oshiumi H, Shime H, Okabe M, Ikawa M, et al. STING in tumor and host cells cooperatively work for NK cell-mediated tumor growth retardation. Biochem Biophys Res Commun. 2016;478:1764–71.
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;7:283ra252.
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;76:2137–52.
Chandra D, Quispe-Tintaya W, Jahangir A, Asafu-Adjei D, Ramos I, Sintim HO, et al. STING ligand c-di-GMP improves cancer vaccination against metastatic breast cancer. Cancer Immunol Res. 2014;2:901–10.
Hayman TJ, Baro M, MacNeil T, Phoomak C, Aung TN, Cui W, et al. STING enhances cell death through regulation of reactive oxygen species and DNA damage. Nat Commun. 2021;12:2327.
Zhu Z, Zhou X, Du H, Cloer EW, Zhang J, Mei L, et al. STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity. Adv Sci. 2023;10:e2203718.
Zheng J, Mo J, Zhu T, Zhuo W, Yi Y, Hu S, et al. Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy. Mol Cancer. 2020;19:133.
Mackenzie KJ, Carroll P, Martin CA, Murina O, Fluteau A, Simpson DJ, et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature. 2017;548:461–5.
Motwani M, Pesiridis S, Fitzgerald KA. DNA sensing by the cGAS-STING pathway in health and disease. Nat Rev Genet. 2019;20:657–74.
Parkes EE, Walker SM, Taggart LE, McCabe N, Knight LA, Wilkinson R, et al. Activation of STING-Dependent Innate Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer. J Natl Cancer Inst. 2017;109:djw199.
Ho SS, Zhang WY, Tan NY, Khatoo M, Suter MA, Tripathi S, et al. The DNA Structure-Specific Endonuclease MUS81 Mediates DNA Sensor STING-Dependent Host Rejection of Prostate Cancer Cells. Immunity. 2016;44:1177–89.
Shen YJ, Le Bert N, Chitre AA, Koo CX, Nga XH, Ho SS, et al. Genome-derived cytosolic DNA mediates type I interferon-dependent rejection of B cell lymphoma cells. Cell Rep. 2015;11:460–73.
Kwon J, Bakhoum SF. The Cytosolic DNA-Sensing cGAS-STING Pathway in Cancer. Cancer Discov. 2020;10:26–39.
Ahn J, Konno H, Barber GN. Diverse roles of STING-dependent signaling on the development of cancer. Oncogene. 2015;34:5302–8.
Ahn J, Xia T, Konno H, Konno K, Ruiz P, Barber GN. Inflammation-driven carcinogenesis is mediated through STING. Nat Commun. 2014;5:5166.
Lemos H, Mohamed E, Huang L, Ou R, Pacholczyk G, Arbab AS, et al. STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation. Cancer Res. 2016;76:2076–81.
Chen Q, Boire A, Jin X, Valiente M, Er EE, Lopez-Soto A, et al. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature. 2016;533:493–8.
Bakhoum SF, Ngo B, Laughney AM, Cavallo JA, Murphy CJ, Ly P, et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature. 2018;553:467–72.
Klarquist J, Hennies CM, Lehn MA, Reboulet RA, Feau S, Janssen EM. STING-mediated DNA sensing promotes antitumor and autoimmune responses to dying cells. J Immunol. 2014;193:6124–34.
Haag SM, Gulen MF, Reymond L, Gibelin A, Abrami L, Decout A, et al. Targeting STING with covalent small-molecule inhibitors. Nature. 2018;559:269–73.
Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015;526:660–5.
Kayagaki N, Kornfeld OS, Lee BL, Stowe IB, O’Rourke K, Li Q, et al. NINJ1 mediates plasma membrane rupture during lytic cell death. Nature. 2021;591:131–6.
Liu J, Yuan L, Ruan Y, Deng B, Yang Z, Ren Y, et al. Novel CRBN-Recruiting Proteolysis-Targeting Chimeras as Degraders of Stimulator of Interferon Genes with In Vivo Anti-Inflammatory Efficacy. J Med Chem. 2022;65:6593–611.
Hsieh JJ, Le VH, Oyama T, Ricketts CJ, Ho TH, Cheng EH. Chromosome 3p Loss-Orchestrated VHL, HIF, and Epigenetic Deregulation in Clear Cell Renal Cell Carcinoma. J Clin Oncol. 2018;36:JCO2018792549.
Cancer Genome Atlas Research N, Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, et al. Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. N Engl J Med. 2016;374:135–45.
Murphy GP, Hrushesky WJ. A murine renal cell carcinoma. J Natl Cancer Inst. 1973;50:1013–25.
Wu J, Chen YJ, Dobbs N, Sakai T, Liou J, Miner JJ, et al. STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death. J Exp Med. 2019;216:867–83.
Zhang H, Zeng L, Xie M, Liu J, Zhou B, Wu R, et al. TMEM173 Drives Lethal Coagulation in Sepsis. Cell Host Microbe. 2020;27:556–70.e556
Demarco B, Grayczyk JP, Bjanes E, Le Roy D, Tonnus W, Assenmacher CA, Radaelli E. Caspase-8–dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality. Sci Adv. 2020;6:eabc3465.
Kwon D, Park E, Kang SJ. Stimulator of IFN genes–mediated DNA-sensing pathway is suppressed by NLRP3 agonists and regulated by mitofusin 1 and TBC1D15, mitochondrial dynamics mediators. FASEB J. 2017;31:4866–78.
Corrales L, Woo S-R, Williams JB, McWhirter SM, Dubensky TW, Gajewski TF. Antagonism of the STING Pathway via Activation of the AIM2 Inflammasome by Intracellular DNA. J Immunol. 2016;196:3191–8.
Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021;384:1289–1300.
Lee C-H, Shah AY, Rasco D, Rao A, Taylor MH, Di Simone C, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol. 2021;22:946–58.
Zhang T, George DJ. Immunotherapy and targeted-therapy combinations mark a new era of kidney cancer treatment. Nat Med. 2021;27:586–8.
Tan Y, Chen Q, Li X, Zeng Z, Xiong W, Li G, et al. Pyroptosis: a new paradigm of cell death for fighting against cancer. J Exp Clin Cancer Res. 2021;40:153.
Acknowledgements
We thank all the patients and their families for their participation. The authors sincerely thank Prof. Tao Li (National Center of Biomedical Analysis, Beijing, China.) for kindly sharing cGAS CRISPR/Cas9 knockout plasmid and Jianjun Chen (Southern Medical University) for sharing SP23 with us. We would like to acknowledge Prof. Feng Shao (National Institute of Biological Sciences, Beijing, China) for kindly sharing GSDMD CRISPR/Cas9 knockout plasmid. This work was supported by National Natural Science Foundation of China (no. 82103594, 82372704,81970665) and Youth Fund of Chinese PLA General Hospital (22QNCZ022).
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XM, YH, and XZ conceived the project, designed the experiments, and wrote the manuscript. SPW, HZL, BJW, HFW performed the experiments. SLD, XH and YF analyzed and interpretated the data. JJC contributed to animal studies. YG, LYG and QBH contributed unpublished essential data and revised the manuscript, and all authors approved the final version of the manuscript.
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Wu, S., Wang, B., Li, H. et al. Targeting STING elicits GSDMD-dependent pyroptosis and boosts anti-tumor immunity in renal cell carcinoma. Oncogene 43, 1534–1548 (2024). https://doi.org/10.1038/s41388-024-03013-4
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DOI: https://doi.org/10.1038/s41388-024-03013-4