生物正交化学
上睑下垂
免疫系统
功能(生物学)
癌症研究
生物
化学
计算生物学
医学
细胞生物学
生物化学
免疫学
组合化学
程序性细胞死亡
细胞凋亡
点击化学
作者
Qinyang Wang,Yupeng Wang,Jingjin Ding,Chunhong Wang,Xuehan Zhou,Wenqing Gao,Huanwei Huang,Feng Shao,Zhibo Liu
出处
期刊:Nature
[Springer Nature]
日期:2020-03-11
卷期号:579 (7799): 421-426
被引量:709
标识
DOI:10.1038/s41586-020-2079-1
摘要
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.
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