Differentiated T Lymphocytes and Cancer Cell Mitochondrial Metabolism to Enhance Radioimmunotherapy by a Biomimetic Nanozyme System

Abstract Strategies to enhance the anti‐tumor immune response through the regulation of cellular metabolism are under intensive investigation. Herein, a T cell membrane (TCM)‐coated biomimetic magnesium carbonate (MgCO ₃ )/Fe‐CD hybrid nanozyme system loaded with the Pyruvate kinase M2 (PKM2) activator TEPP‐46 (TFMP) is developed, designed to simultaneously induce mitochondrial metabolic reprogramming in both T cells and tumor cells following radiotherapy (RT). The TCM coating enables TFMP to specifically target tumor tissues that highly express PD‐L1, where it competitively binds to PD‐L1 and thereby alleviates immune checkpoint‐mediated T cell suppression. Upon X‐ray irradiation, TFMP continuously catalyzes the conversion of radiotherapy‐generated hydrogen peroxide into hydroxyl radicals, thereby sustaining reactive oxygen species production, which leads to mitochondrial damage and immunogenic cell death in tumor cells. Moreover, TFMP can neutralize the acidic tumor microenvironment, while the released Mg ²⁺ and TEPP‐46 further augment T cell activation and mitochondrial function, thereby increasing the production of ATP and granzyme B, which effectively eliminate residual tumor cells. Experimental results demonstrate that the combination of TFMP and RT can significantly inhibit tumor progression and activate anti‐tumor immunotherapy. This TFMP enhances the efficacy of breast cancer radioimmunotherapy, offering a foundation for developing more comprehensive therapeutic approaches of breast cancer to achieve clinical benefits.