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Targeting STING elicits GSDMD-dependent pyroptosis and boosts anti-tumor immunity in renal cell carcinoma

Oncogene (2024)Cite this article

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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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Fig. 1: Upregulation of STING in RCC patients correlates with poor prognosis.
Fig. 2: STING Inhibition selectively targets renal cancer cells.
Fig. 3: Biological function of STING is independent of its role in innate immune signaling or proangiogenic factors in RCC.
Fig. 4: STING knockdown in RCC cells results in the inhibition of protein synthesis.
Fig. 5: STING represses ER stress and UPR activation to promote tumor survival.
Fig. 6: Loss of STING mediated GSDMD-dependent pyroptosis through activation of Caspase-8.
Fig. 7: The induction of antitumor immunity through pyroptosis-induced inflammation is observed following STING knockdown.
Fig. 8: Targeting STING by SP23 can also induce renal cancer cell pyroptosis and promote antitumor immunity.

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Data availability

All datasets and raw data generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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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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  1. These authors contributed equally: Shengpan Wu, Baojun Wang, Hongzhao Li.

Authors and Affiliations

  1. Department of Urology, The Third Medical Center, Chinese PLA General Hospital, 100853, Beijing, China

    Shengpan Wu, Baojun Wang, Hongzhao Li, Hanfeng Wang, Songliang Du, Xing Huang, Yang Fan, Yu Gao, Liangyou Gu, Qingbo Huang, Xu Zhang, Yan Huang & Xin Ma

  2. School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China

    Jianjun Chen

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Contributions

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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Correspondence to Xu Zhang, Yan Huang or Xin Ma.

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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 (2024). https://doi.org/10.1038/s41388-024-03013-4

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