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.

Keywords

anion-π⁺ / ferroptosis / lung metastasis / photodynamic immunotherapy

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RIGHTS & PERMISSIONS

2026 The Author(s). Aggregate published by SCUT, AIEI, and John Wiley & Sons Australia, Ltd.