Singlet oxygen-precharged injectable hydrogel triggers ferroptosis and lactate metabolism reprogramming for enhanced colorectal cancer immunotherapy

Photodynamic therapy (PDT) holds significant potential for tumor treatment, yet its immunotherapeutic efficacy is severely constrained by the immunosuppressive tumor microenvironment (TME) marked by lactate accumulation, hypoxia, and glutathione (GSH) overexpression. To overcome these limitations, we engineered an injectable hydrogel system (FPH@A/C) that synergistically integrates oxygen-independent PDT, ferroptosis activation, and lactate metabolic reprogramming to remodel immunosuppressive TME and potentiate antitumor immunity. The hydrogel comprises singlet oxygen-preloaded iron-based nanoparticles (FPH), lithium carbonate (LC), and sodium alginate (ALG), rapidly crosslinking into a stable matrix when encountering physiological Ca²⁺ concentration for localized therapeutic delivery. Within TME, GSH-triggered FPH degradation releases Fe²⁺ and pre-stored singlet oxygen, enabling chemodynamic therapy (CDT) and photo-independent PDT to induce tumor ferroptosis. Simultaneously, LC reprograms lactate-a metabolic byproduct-into an energy substrate for CD8⁺ T cells, counteracting lactate-driven immunosuppression. Notably, combining FPH@A/C with immune checkpoint blockade (ICB) therapy demonstrates synergistic effects, robustly enhancing dendritic cell maturation and cytotoxic T lymphocyte infiltration. This multifunctional platform establishes a novel paradigm for colorectal cancer immunotherapy by concurrently addressing metabolic constraints and immune evasion mechanisms.