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A bioorthogonal system reveals antitumour immune function of pyroptosis

Author

Listed:
  • Qinyang Wang

    (Peking University)

  • Yupeng Wang

    (Chinese Academy of Medical Sciences
    National Institute of Biological Sciences)

  • Jingjin Ding

    (National Institute of Biological Sciences
    Institute of Biophysics, Chinese Academy of Sciences)

  • Chunhong Wang

    (Peking University)

  • Xuehan Zhou

    (Peking University)

  • Wenqing Gao

    (National Institute of Biological Sciences)

  • Huanwei Huang

    (National Institute of Biological Sciences)

  • Feng Shao

    (Chinese Academy of Medical Sciences
    National Institute of Biological Sciences
    Tsinghua University)

  • Zhibo Liu

    (Peking University
    Peking University)

Abstract

Bioorthogonal chemistry capable of operating in live animals is needed to investigate biological processes such as cell death and immunity. Recent studies have identified a gasdermin family of pore-forming proteins that executes inflammasome-dependent and -independent pyroptosis1–5. Pyroptosis is proinflammatory, but its effect on antitumour immunity is unknown. Here we establish a bioorthogonal chemical system, in which a cancer-imaging probe phenylalanine trifluoroborate (Phe-BF3) that can enter cells desilylates and ‘cleaves’ a designed linker that contains a silyl ether. This system enabled the controlled release of a drug from an antibody–drug conjugate in mice. When combined with nanoparticle-mediated delivery, desilylation catalysed by Phe-BF3 could release a client protein—including an active gasdermin—from a nanoparticle conjugate, selectively into tumour cells in mice. We applied this bioorthogonal system to gasdermin, which revealed that pyroptosis of less than 15% of tumour cells was sufficient to clear the entire 4T1 mammary tumour graft. The tumour regression was absent in immune-deficient mice or upon T cell depletion, and was correlated with augmented antitumour immune responses. The injection of a reduced, ineffective dose of nanoparticle-conjugated gasdermin along with Phe-BF3 sensitized 4T1 tumours to anti-PD1 therapy. Our bioorthogonal system based on Phe-BF3 desilylation is therefore a powerful tool for chemical biology; our application of this system suggests that pyroptosis-induced inflammation triggers robust antitumour immunity and can synergize with checkpoint blockade.

Suggested Citation

  • Qinyang Wang & Yupeng Wang & Jingjin Ding & Chunhong Wang & Xuehan Zhou & Wenqing Gao & Huanwei Huang & Feng Shao & Zhibo Liu, 2020. "A bioorthogonal system reveals antitumour immune function of pyroptosis," Nature, Nature, vol. 579(7799), pages 421-426, March.
  • Handle: RePEc:nat:nature:v:579:y:2020:i:7799:d:10.1038_s41586-020-2079-1
    DOI: 10.1038/s41586-020-2079-1
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    Citations

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    Cited by:

    1. Xianghan Zhang & Jingkai Gao & Yingdi Tang & Jie Yu & Si Si Liew & Chaoqiang Qiao & Yutian Cao & Guohuan Liu & Hongyu Fan & Yuqiong Xia & Jie Tian & Kanyi Pu & Zhongliang Wang, 2022. "Bioorthogonally activatable cyanine dye with torsion-induced disaggregation for in vivo tumor imaging," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Fengqiao Li & Xue-Qing Zhang & William Ho & Maoping Tang & Zhongyu Li & Lei Bu & Xiaoyang Xu, 2023. "mRNA lipid nanoparticle-mediated pyroptosis sensitizes immunologically cold tumors to checkpoint immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Zhaoting Li & Fanyi Mo & Yixin Wang & Wen Li & Yu Chen & Jun Liu & Ting-Jing Chen-Mayfield & Quanyin Hu, 2022. "Enhancing Gasdermin-induced tumor pyroptosis through preventing ESCRT-dependent cell membrane repair augments antitumor immune response," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Chaiheon Lee & Mingyu Park & W. C. Bhashini Wijesinghe & Seungjin Na & Chae Gyu Lee & Eunhye Hwang & Gwangsu Yoon & Jeong Kyeong Lee & Deok-Ho Roh & Yoon Hee Kwon & Jihyeon Yang & Sebastian A. Hughes , 2024. "Oxidative photocatalysis on membranes triggers non-canonical pyroptosis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Zhigui Zuo & Hao Yin & Yu Zhang & Congying Xie & Qinyang Wang, 2023. "A cytotoxic T cell inspired oncolytic nanosystem promotes lytic cell death by lipid peroxidation and elicits antitumor immune responses," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Liang Zhang & An Song & Qi-Chao Yang & Shu-Jin Li & Shuo Wang & Shu-Cheng Wan & Jianwei Sun & Ryan T. K. Kwok & Jacky W. Y. Lam & Hexiang Deng & Ben Zhong Tang & Zhi-Jun Sun, 2023. "Integration of AIEgens into covalent organic frameworks for pyroptosis and ferroptosis primed cancer immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    7. Xionghui Ding & Hiroto Kambara & Rongxia Guo & Apurva Kanneganti & Maikel Acosta-Zaldívar & Jiajia Li & Fei Liu & Ting Bei & Wanjun Qi & Xuemei Xie & Wenli Han & Ningning Liu & Cunling Zhang & Xiaoyu , 2021. "Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    8. Yuan Lu & Wenbo He & Xin Huang & Yu He & Xiaojuan Gou & Xiaoke Liu & Zhe Hu & Weize Xu & Khaista Rahman & Shan Li & Sheng Hu & Jie Luo & Gang Cao, 2021. "Strategies to package recombinant Adeno-Associated Virus expressing the N-terminal gasdermin domain for tumor treatment," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    9. Stefania A. Mari & Kristyna Pluhackova & Joka Pipercevic & Matthew Leipner & Sebastian Hiller & Andreas Engel & Daniel J. Müller, 2022. "Gasdermin-A3 pore formation propagates along variable pathways," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    10. Sheng-Yan Huang & Sha Gong & Yin Zhao & Ming-Liang Ye & Jun-Yan Li & Qing-Mei He & Han Qiao & Xi-Rong Tan & Jing-Yun Wang & Ye-Lin Liang & Sai-Wei Huang & Shi-Wei He & Ying-Qin Li & Sha Xu & Ying-Qing, 2024. "PJA1-mediated suppression of pyroptosis as a driver of docetaxel resistance in nasopharyngeal carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    11. Yaxin Shi & Zhibin Guo & Qiang Fu & Xinyuan Shen & Zhongming Zhang & Wenjia Sun & Jinqiang Wang & Junliang Sun & Zizhu Zhang & Tong Liu & Zhen Gu & Zhibo Liu, 2023. "Localized nuclear reaction breaks boron drug capsules loaded with immune adjuvants for cancer immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    12. Jing Lin & Shihui Sun & Kui Zhao & Fei Gao & Renling Wang & Qi Li & Yanlong Zhou & Jing Zhang & Yue Li & Xinyue Wang & Le Du & Shuai Wang & Zi Li & Huijun Lu & Yungang Lan & Deguang Song & Wei Guo & Y, 2023. "Oncolytic Parapoxvirus induces Gasdermin E-mediated pyroptosis and activates antitumor immunity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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