Probing-to-perturbing: Imaging-guided localized desilylation induces gasdermin release and pyroptotic cell death activates antitumor immunity

Objectives: Bioorthogonal chemistry capable of operating in the living system is badly needed for dissecting complex biological processes like cell death and immunity. Recent studies in innate immunity identify a gasdermin family of pore-forming proteins that executes inflammasome-dependent or -independent pyroptosis. Pyroptosis is proinflammatory but its exact immunologic effect in disease contexts, such as cancer immunity, is unclear. Here we established a bioorthogonal chemical system (i.e., a cell-enterable cancer-imaging probe Phe-BF3 specifically desilylates and “cleaves” a silyl ether and carbamate-containing linker). When the linker was attached to the gold nanoparticle (NP) vehicle, the system showed a selective tumor targeting in mice and readily released the client GFP protein from the endocytosed NPs. Application of the system to a gasdermin triggered cell pyroptosis at the final execution step. In mice, tumor cell pyroptosis induced by Phe-BF3-released gasdermin causes nearly complete regression of implanted tumorgrafts including the 4T1 mammary carcinoma. This effect requires pore-forming activity of the gasdermin and occurs with both intravenous and intratumoral injection of Phe-BF3 and the NP-gasdermin conjugate. Pyroptosis-induced tumor regression is blocked in immune-deficient nude mice or upon T-cell depletion, and correlates with increased tumor-infiltrating lymphocytes. An ineffective injection regimen with only one round of pyroptosis induction prominently sensitizes the 4T1 tumors to anti-PD1 therapy. Thus, our desilylation-based bioorthogonal system is a powerful chemical biology tool; its application reveals that pyroptosis-induced inflammation can trigger effective antitumor immunity or improve the efficacy of checkpoint blockade immunotherapy.