Immune‐Engineered Hydrogels Combat Orthotopic and Metastatic Cancer via Hypoxia‐Relieved Photodynamic Therapy and Ferroptotic Cell Death

ABSTRACT Hypoxia severely impairs photodynamic therapy (PDT) by limiting oxygen availability and activating HIF‐1α‐mediated immunosuppressive pathways. Herein, we develop fully functional immune hydrogels (AV@PFgel) that synergistically integrate hypoxia relief, ferroptosis induction, and violet phosphorus nanosheet (VPN)‐induced PDT within a single therapeutic platform to potentiate antitumor immunity. The dual‐crosslinked AV@PFgel degrades in acidic tumor microenvironment (TME) to enable oxygen generation and Fenton reaction‐mediated ferroptosis through released PolyMet, Fe 3+ , and acriflavine (ACF)‐loaded VPN, jointly promoting immunogenic cell death (ICD). VPN, acting as a potent photosensitizer, triggers PDT for direct tumor ablation and ICD induction, whereas ACF‐mediated HIF‐1α inhibition counteracts hypoxia‐associated immunosuppression. Notably, AV@PFgel reprograms the TME into an immunostimulatory state, eliciting durable local and systemic antitumor immune responses. Consequently, a single intratumoral administration of AV@PFgel combined with regular laser irradiation markedly suppresses primary and metastatic triple‐negative breast cancer, highlighting its translational promise for long‐term cancer immunotherapy. Collectively, this work presents a versatile and integrated strategy to overcome the hypoxia barrier while coordinately activating both innate and adaptive immune responses, paving the way for advanced cancer immunotherapy with improved and durable efficacy.