Composite Hydrogel for Spatiotemporal Lipid Intervention of Tumor Milieu

Abstract Induction of immunogenic cell death (ICD) plays crucial roles in cancer immunotherapy, whereas its efficacy is severely compromised by redundant antioxidant defenses in cancer cells and aberrant lipid metabolism in immunosuppressive cell populations. In this work, it is found that hollow mesoporous CuS nanoparticles (NPs) possess an intrinsic capacity of inhibiting glutathione peroxidase 4 (GPX4). When loaded with an inhibitor of the ferroptosis suppressor protein 1 (FSP1), these NPs block two parallel redox systems and cooperate with near‐infrared irradiation to reinforce ICD. A hydrogel co‐delivering cancer‐cell‐targeting CuS NPs and immunosuppressive‐cell‐targeting sulfo‐N‐succinimidyl oleate (SSO) for spatiotemporal lipid intervention i further fabricated. While the CuS NPs augment ICD via synergistic lipid peroxidation, SSO reinstates immune perception via lipid metabolic reprogramming, thereby coordinately triggering robust innate and adaptive immunity to restrain tumor growth, relapse, and metastasis. This study provides an immunometabolic therapy via orchestrated lipid modulation in the tumor milieu.