Multi‐Enzyme Nanoparticles as Efficient Pyroptosis and Immunogenic Cell Death Inducers for Cancer Immunotherapy

Immunotherapy represents a widely employed modality in clinical oncology, leveraging the activation of the human immune system to target and eradicate cancer cells and tumor tissues via endogenous immune mechanisms. However, its efficacy remains constrained by inadequate immune responses within “cold” tumor microenvironment (TME). In this study, a multifunctional nanoscale pyroptosis inducer with cascade enzymatic activity (IMZF), comprising superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and glutathione oxidase (GSHOx), is dissociated within the acidic and glutathione‐rich TME. The vigorous enzymatic activity not only generates oxygen (O2) to alleviate hypoxia and promote M2 to M1 macrophage polarization but also yields reactive oxygen species (ROS) and depletes glutathione (GSH) within the TME. Functioning as an immunogenic cell death (ICD) activator and pyroptosis inducer, IMZF synergistically triggers dendritic cell maturation and inflammatory lymphocyte infiltration via ICD‐associated pyroptosis, thereby reversing immune suppression within the TMEs. Consequently, it exerts inhibitory effects on both primary and distal tumors. This cascade enzymatic platform‐based pyroptosis inducer offers an intelligent strategy for effectively overcoming immune suppression within “cold” tumors, thereby providing a promising avenue for advanced immunotherapeutic interventions. An ICD and pyroptosis‐induced nanoenzyme is first proposed for efficient tumor immunotherapy. The nanoenzyme IMZF demonstrates the SOD, CAT, POD, and GSHOx‐like catalytic ability; then thus, facilitating ROS generation, depleting GSH, and arousing ICD/pyroptosis pathways for efficient antigen presentation. This work provides a new design strategy for simultaneously enhancing antigen presentation and for reversal of immune suppression TME.