Augmenting Immunotherapy via Bioinspired MOF‐Based ROS Homeostasis Disruptor with Nanozyme‐Cascade Reaction

Abstract Despite its remarkable clinical breakthroughs, immune checkpoint blockade (ICB) therapy remains limited by the insufficient immune response in the “cold” tumor. Nanozyme‐based antitumor catalysis is associated with precise immune activation in the tumor microenvironment (TME). In this study, a cascade‐augmented nanoimmunomodulator (CMZM) with multienzyme‐like activities, which includes superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and glutathione oxidase (GSHOx), that dissociates under an acidic and abundant GSH TME, is proposed for multimodal imaging‐guided chemodynamic therapy (CDT)/photodynamic therapy (PDT) enhanced immunotherapy. Vigorous multienzyme‐like activities can not only produce O₂ to alleviate hypoxia and promote the polarization of M2 to M1 macrophages, but also generate ROS (•OH and ¹O₂) and deplete GSH in the TME to expose necrotic cell fragments and reverse immunosuppressive TME by eliciting the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes (CTLs) in tumors. Therefore, inhibitory effects on both primary and distant tumors are achieved through synergy with an α‐PD‐L1 blocking antibody. This cascade multienzyme‐based nanoplatform provides a smart strategy for highly efficient ICB immunotherapy against “cold” tumors by revising immunosuppressive TME.