Bioorthogonal-Activated In Situ Vaccine Mediated by a COF-Based Catalytic Platform for Potent Cancer Immunotherapy.

Personalized tumor vaccines have become a promising modality for cancer immunotherapy. However, in situ personalized tumor vaccines generated from immunogenic cancer cell death (ICD) and adjuvants are mired by toxic side effects and unsatisfactory efficiency. Herein, by functionalizing the reticular structure to optimize the catalytic activity of the materials, a series of biocompatible covalent organic framework (COF)-based catalysts have been designed and screened for establishing a bioorthogonal-activated in situ cancer vaccine in an efficient and safe way. Especially, pro-doxorubicin (pro-DOX) could be bioorthogonally activated in situ by the COF-based Fe(II) catalysts, which elicited ICD and released tumor-associated antigens (TAAs). This in situ prodrug activation strategy could minimize drug side effects and maximize treatment effects. More importantly, the system could also catalytically activate pro-imiquimod (pro-IMQ, a TLR7/8 immune agonist), which served as an adjuvant to amplify the antitumor immunity. Notably, this bioorthogonal-activated in situ cancer vaccine not only facilitated a strong antitumor immune response but also prevented the dose-dependent side effects of chemotherapeutic drugs, including systemic inflammation caused by the random distribution of adjuvants. To the best of our knowledge, it is the first time to devise an efficient catalytic platform for generating an in situ bioorthogonal-activated cancer vaccine, which would provide a paradigm for achieving secure and robust immunotherapy.