Composite Hydrogel for Spatiotemporal Lipid Intervention of Tumor Milieu.

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. Herein, we find that hollow mesoporous CuS nanoparticles (NPs) possess an intrinsic capacity of inhibiting the 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. We further fabricate a hydrogel co-delivering cancer cell-targeting CuS NPs and immunosuppressive cell-targeting sulfo-N-succinimidyl oleate (SSO) for spatiotemporal lipid intervention. 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. Our study provides an immunometabolic therapy via orchestrated lipid modulation in the tumor milieu. This article is protected by copyright. All rights reserved.