An Activity-Reinforced P-Modified Single-Atom Cu Nanozyme Potentiates IDO Blockade-Induced Tumor Radiotherapy

Radiotherapy exerts both immunostimulatory and immunosuppressive effects on breast cancer (BRCA), limiting its therapeutic potential. To shift this balance toward a more favorable antitumor immune response, an indoleamine 2,3-dioxygenase 1 (IDO1)-blocking nanozyme specifically designed to potentiate tumor radioimmunotherapy was developed. Using a ZnO-carbon nanoframework, single Cu-N₄ catalytic sites were engineered to construct a single-atom Cu nanozyme (SAzyme) exhibiting dual peroxidase- and catalase-mimicking activities for the delivery of the IDO1 inhibitor 1-methyl-tryptophan (1-MT), resulting in a platform termed CPMR. Phosphorus modification further improved the catalytic performance of the SAzyme. Once internalized by tumor cells, CPMR generates sufficient oxygen to alleviate hypoxia and improve radiosensitivity while simultaneously inducing oxidative stress to promote tumor cell death and trigger immunogenic cell death. These events facilitate the recruitment and activation of tumor-infiltrating cytotoxic T lymphocytes. The controlled release of 1-MT inhibits IDO1 activity and reduces L-tryptophan levels, suppressing regulatory T-cell function and mitigating the immunosuppressive tumor microenvironment. These mechanisms synergistically improve the efficacy of radiotherapy against BRCA. CPMR represents a promising tumor-reprogramming strategy capable of eliciting a robust antitumor immune response and significantly strengthening radiotherapeutic outcomes in patients with breast cancer.