Anion‐π ⁺ Type AIE‐Active Photosensitizers for Ferroptosis‐Driven Photodynamic Immunotherapy Against Hypoxic Solid Tumors

ABSTRACT Photodynamic immunotherapy holds great promise in tumor treatment by activating immune memory to surveil and eradicate recurrent/metastatic tumor cells. However, its efficacy against hypoxic solid tumors remains significantly limited due to oxygen dependency, apoptosis resistance, and immunosuppressive tumor microenvironment (TME). Herein, a facile strategy of anion‐π + interactions was proposed to fabricate Type I photosensitizers (PSs) to achieve ferroptosis‐driven photodynamic immunotherapy against hypoxic solid tumors. By introducing anion‐π + interaction, aggregation‐induced emission (AIE)‐active TMTPA with near‐infrared emission was developed and encapsulated into nanoparticles (NPs). Under 635 nm laser irradiation, TMTPA NPs demonstrated superior Type I reactive oxygen species (ROS) generation and exceptional mitochondrial targeting, causing lipid peroxidation accumulation and triggering ferroptosis. This further promoted dendritic cell (DC) maturation and stimulated T cell proliferation, thereby amplifying systemic antitumor immunity. Ultimately, TMTPA NPs achieved 86% inhibition of the primary tumor and effective suppression of lung metastasis. This work presents a novel anion‐π + Type I PS that induces ferroptosis and reprograms the immunosuppressive TME, offering a promising strategy for combating hypoxic solid tumors.