Summary                         

Bioorthogonal chemistry capable of operating in live animals is needed to investigate biological processes such as cell death and immunity. Recent studies have identifed a gasdermin family of pore-forming proteins that executes infammasome-dependent and -independent pyroptosis. Pyroptosis is proinfammatory, but its efect on antitumour immunity is unknown. Here a bioorthogonal chemical system is established, in which a cancer-imaging probe phenylalanine trifuoroborate (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. This bioorthogonal system was applied to gasdermin, which revealed that pyroptosis of less than 15% of tumour cells was sufcient to clear the entire 4T1 mammary tumour graft. The tumour regression was absent in immune-defcient mice or upon T cell depletion, and was correlated with augmented antitumour immune responses. The injection of a reduced, inefective dose of nanoparticle-conjugated gasdermin along with Phe-BF₃ sensitized 4T1 tumours to anti-PD1 therapy. This bioorthogonal system based on Phe-BF₃ desilylation is therefore a powerful tool for chemical biology; the application of this system suggests that pyroptosis-induced infammation triggers robust antitumour immunity and can synergize with checkpoint blockade.

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