Self-oxygenating nanoreactors enable effective low-dose X-ray photodynamic immunotherapy against refractory tumors.

Although low-dose radiotherapy (LDRT) exhibits high potential for radiotherapy, it meets a cascade of limitations for effectively eradicating refractory tumors due to low cell-killing effects, insufficient reactive oxygen species (ROS) production and acquired radio-resistance. Here, we engineered a new type of self-oxygenating nanoreactor (HCCP) to relieve hypoxia and effectively eradicate radio-resistant triple-negative breast cancer (TNBC) by combining low-dose X-ray-induced photodynamic therapy (LX-PDT), cuproptosis and chemodynamic therapy (CDT), which was further discovered to trigger the stimulator of interferon genes (STING) pathway for immunotherapy. HCCP was engineered by self-assembling hyaluronic acid-shielded ultrasmall calcium peroxide nanodots onto Cu-porphyrin coordinated core nanoparticles. HCCP can target breast cancer cells to supply O2 and H2O2 to relieve hypoxia, generate ROS, and induce cuproptosis and apoptosis by Cu, CDT and LX-PDT. By i.v. injection, HCCP exhibited high tumor accumulation and alleviated tumor hypoxia, leading to effective eradication of conventional, large and radio-resistant TNBC upon low-dose X-ray irradiation with promoted survival rates. Additionally, HCCP was further found to activate STING and elicit robust antitumor immunity for potently inhibiting distant and metastatic TNBC. Collectively, this study presents an effective nanoreactor-based strategy to overcome the limitations of LDRT for potently treating refractory TNBC malignancies, and highlights its potential for further translational development.