Microenvironmental Self‐Optimizing HOFs Biocatalysts for Boosting Disulfidptosis‐Mediated Antitumor Immunotherapy

Abstract Disulfidptosis, a novel programmed cell death mechanism triggered by glucose deprivation in solute carrier family 7 member 11 (SLC7A11)‐overexpressing tumors, facilitates the release of tumor‐associated antigens (TAAs) and activates immune responses, providing a new strategy to enhance immunotherapy by converting redox vulnerabilities into immunogenic opportunities. Herein, a hydrogen‐bonded organic frameworks (HOFs)‐based cascade biocatalyst is constructed to boost disulfidptosis‐mediated antitumor immunotherapy. Engineered via charge‐mediated assembly, peroxidase‐mimetic iron‐porphyrin HOFs are integrated with glucose oxidase (GOx) to establish a microenvironmental self‐optimizing catalytic network. The HOFs architecture not only enhances GOx stability but also converts enzymatically generated H 2 O 2 into cytotoxic hydroxyl radicals. Simultaneously, GOx‐mediated glucose depletion acidifies the catalytic cavity microenvironment within HOFs, thereby amplifying catalytic efficiency. This biocatalysis system disrupts redox homeostasis, induces glucose deprivation, and activates disulfidptosis. By coupling immunogenic antigen release with oxidative damage, the platform transforms redox vulnerabilities into immune‐activating signals, effectively converting “cold” tumors into immunologically active states. This molecularly engineered approach pioneers the construction strategy of cavity self‐acidized HOFs‐based biocatalysts that harmonize divergent catalytic conditions, enabling cross‐scale biocatalysis, and offers a paradigm shift in cancer immunotherapy by integrating metabolic intervention, immunogenic cell death, and microenvironment remodeling into a unified therapeutic strategy.