Tumor Microenvironment Reprogramming via Copper-Enriched Black Phosphorus Nanoplatform for Cuproptosis-Sensitized Low-Dose Radioimmunotherapy.

Objective: Radioimmunotherapy (RIT) is a promising treatment for deep-seated and metastatic tumors, but its efficacy is limited by the immunosuppressive tumor microenvironment (TME) and a narrow therapeutic window. This study aimed to develop a novel nanoplatform to overcome these constraints by simultaneously sensitizing tumors to radiation, inducing cuproptosis, and reprogramming the immunosuppressive TME. Methods: We engineered a PEGylated copper-loaded black phosphorus nanoplatform (BPNS@Cu-PEG). Its functionality as a radiosensitizer and cuproptosis inducer was evaluated. The mechanisms of TME reprogramming were investigated, including glutathione (GSH) depletion, reactive oxygen species (ROS) amplification, hypoxia alleviation, and M2-to-M1 macrophage repolarization. Furthermore, we systematically evaluated its antitumor immune effects in vitro and in vivo. Results: BPNS@Cu-PEG was synthesized with a high copper incorporation rate of 93%. In vitro cellular assays confirmed that the internalized nanoplatform effectively induced cuproptosis and immunogenic cell death (ICD) while simultaneously regulating the TME. In vivo, BPNS@Cu-PEG not only potently inhibited tumor progression and stimulated robust antitumor immunity under low-dose radiotherapy but also exhibited an excellent safety profile. Conclusion: This work establishes a copper-based, low-dose radioimmunotherapy strategy. The BPNS@Cu-PEG nanoplatform presents a viable and potent strategy to counteract radioresistance and promote systemic antitumor immunity, potentially broadening the therapeutic application and safety profile of RIT.