A Self-Reinforcing Cuproptosis−Radiotherapy Loop by Copper Carbonate Nanoparticles for Enhanced Immunotherapy

Abstract

Radiotherapy leverages radiation-induced immunogenic cell death (ICD) to boost antitumor immunity, showing great potential for localized cancer therapy. However, its immunostimulatory efficacy is limited by suboptimal immunogenicity and the immunosuppressive tumor microenvironment (TME). Herein, we developed a multifunctional therapeutic platform based on copper carbonate nanoparticles (CuCO3@PEG) for enhanced antitumor immunity via remodeling TME and establishing a self-reinforcing cuproptosis−radiotherapy loop. CuCO3@PEG remodels the immunosuppressive TME by neutralizing H+, depleting lactic acid and alleviating hypoxia, thus enhancing RT and avoiding immune escape. Mechanistic studies revealed that cuproptosis induced by the released copper ions specifically downregulated the cyclin-dependent kinase 1 (CDK1), inducing G2/M phase arrest in tumor cells and thereby achieving cell cycle-synchronized radiosensitization. Notably, radiotherapy suppressed the expression of ATPase copper transporting alpha (ATP7A), creating a copper-locking effect and establishing a bidirectional positive feedback loop where radiotherapy enhanced cuproptosis, and cuproptosis sensitized tumor cells to radiotherapy. This synergistic mechanism induced potent ICD, transforming the tumor into an in situ vaccine through damage-associated molecular patterns release. Coupled with TME remodeling, this process significantly augmented antitumor immunity and prevented tumor recurrence. The work provides a promising cuproptosis−radiotherapy synergy strategy to overcome the challenges of radioresistance and immunosuppression in cancer treatment.