γ-Radionuclide Technetium-99M Activated Long-Lasting Chemodynamic Therapy and Immunogenic Brachytherapy for Enhanced Antitumor Immunity.

Abstract

Chemodynamic therapy (CDT) and brachytherapy face critical challenges, particularly the limited efficiency of Fenton reaction and the insufficient antitumor immunogenicity of brachytherapy. In this study, we employ the metal-organic framework nanocomposite Hf-TCPP@Fe-^99mTc (where TCPP = tetrakis(4-carboxyphenyl) porphyrin and ^99mTc = technetium-99m) for synergistic long-lasting CDT and immunogenic brachytherapy. Benefiting from the robust interaction between ^99mTc-emitted γ-rays and the high-Z element Hf, the secondary electrons generated during brachytherapy not only damage tumor cells but also establish an electron-rich microenvironment that drives the continuous reduction of Fe³⁺ to Fe²⁺, thereby sustaining a highly efficient Fenton reaction. With the generation of hydroxyl radical persisting for over 12 h, this synergistic effect reduced cell viability by an additional 28.6% beyond projections, thereby inducing effective immunogenic cell death, activating a systemic antitumor immune response, and inhibiting both primary and metastatic triple-negative breast cancer. Through rational design, this work demonstrates that clinically prevalent nontherapeutic γ-radionuclide can activate long-lasting CDT and immunogenic brachytherapy to enhance antitumor immunogenicity.