K2FeO4‐Enhanced Photodynamic Therapy of Breast Cancer via In Situ Synthesis of Fe2O3 and O2

Abstract Photodynamic Therapy (PDT) offers a promising minimally invasive treatment for breast cancer, but its efficacy is limited by the hostile tumor microenvironment (TME), including hypoxia and high glutathione (GSH) levels. Although various strategies to improve oxygen concentration or reduce reactive oxygen species (ROS) resistance for enhanced PDT have been explored, they typically require intricate design and complex synthesis of multifunctional nanocarriers. Thus, this study introduces a facile K 2 FeO 4 ‐induced strategy to enhance PDT efficiency in breast cancer through the tumor in situ synthesis of Fe 2 O 3 and O 2 . Inspired by the successful application of K 2 FeO 4 in ecological remediation and hemostasis, K 2 FeO 4 reacts with GSH, biological system, H 2 O 2 , and water, to generate Fe 2 O 3 and O 2 . Intratumoral injection of K 2 FeO 4 improves the TME, followed by Ce6 administration to enhance PDT through synergistic ferroptosis. This approach boosts PDT efficacy significantly by increasing ROS generation, lipid peroxidation, and inhibiting GSH and GPX4. Proteomic analysis revealed alterations in key pathways, including endocytosis and energy metabolism. This K 2 FeO 4 ‐PDT strategy creates a positive feedback loop by enhancing oxidative stress, providing an interesting and promising approach to PDT.