Engineering Multienzyme-Mimicking Covalent Organic Frameworks as Pyroptosis Inducers for Boosting Antitumor Immunity.

The engineering of a series of multienzyme-mimicking covalent organic frameworks (COFs), COF-909-Cu, COF-909-Fe, and COF-909-Ni, as pyroptosis inducers, remodeling the tumor microenvironment to boost cancer immunotherapy, is reported. Mechanistic studies reveal that these COFs can serve as hydrogen peroxide (H 2 O 2 ) homeostasis disruptors to elevate intracellular H 2 O 2 levels, and they not only exhibit excellent superoxide dismutase (SOD)-mimicking activity and convert superoxide radicals (O 2 •- ) to H 2 O 2 to facilitate H 2 O 2 generation, but also possess outstanding glutathione peroxidase (GPx)-mimicking activity and deplete glutathione (GSH) to alleviate the scavenging of H 2 O 2 . Meanwhile, the outstanding photothermal therapy properties of these COFs can accelerate the Fenton-like ionization process to facilitate their chemodynamic therapy efficiency. One member, COF-909-Cu, can robustly induce gasdermin E (GSDME)-dependent pyroptosis and remodel the tumor microenvironment to trigger durable antitumor immunity, thus promoting the response rate of αPD-1 checkpoint blockade and successfully restraining tumor metastasis and recurrence.