Copper-Induced Cuproptosis and Immunogenic Cell Death Synergize with Radiotherapy and PD-1 Blockade in Osteosarcoma

Radiotherapy (RT) is a widely used clinical treatment for cancer, leveraging ionizing radiation; however, some patients exhibit resistance to radiation due to insufficient reactive oxygen species (ROS) production. Copper-based nanomaterials represent a promising class of antitumor agents capable of generating abundant ROS. In this study, R837 and Cu_2–xSe were incorporated into PLGA (50:50)_20k-PEG_2k-iRGD to develop a targeted nanomaterial for tumor therapy. These nanoparticles effectively induced cuproptosis, inhibited tumor cell proliferation, remodeled the tumor immune microenvironment (TME), and promoted immunogenic cell death (ICD), thereby enhancing the efficacy of PD-1 checkpoint blockade therapy (αPD-1). Furthermore, our results demonstrated that the Cu_2–xSe(R837)-iRGD nanoformulations, in combination with radiotherapy, promoted the infiltration of CD8⁺ T cells and activated antitumor immune responses in vivo. In conclusion, our study confirmed that Cu_2–xSe(R837)-iRGD nanoformulations combined with radiotherapy yielded promising therapeutic outcomes and held potential for clinical application in osteosarcoma (OS) treatment.