Radiation-Triggered Alkyl Free Radical Generator for the Oxygen-Independent Radioimmunotherapy of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a subtype of breast cancer frequently associated with poor clinical outcomes. TNBC commonly exhibits a hypoxic tumor microenvironment that limits oxidative damage induced by reactive oxygen species (ROS), thereby reducing the effectiveness of dynamic therapy (DT). To address this challenge, the nanoradiosensitizer AIBN@F127 was developed to enable radiation-triggered free radical generation capable of inducing immunogenic cell death (ICD) for the radioimmunotherapy of TNBC. Upon X-ray irradiation, AIBN@F127 generates alkyl free radicals under both normoxic and hypoxic conditions, resulting in DNA damage, enhanced apoptosis, and improved anticancer efficacy. Our approach of radiotherapy with AIBN@F127 effectively amplifies ICD and promotes immune cell infiltration into tumors, potentially improving the outcomes of immunotherapy. Moreover, the combination of AIBN@F127-mediated irradiation with a programmed death ligand-1 inhibitor demonstrates promise in eliciting robust antitumor immune responses. Overall, this study presents an effective all-in-one strategy employing a radiation-triggered alkyl free radical generator to overcome key limitations in the treatment of hypoxic solid tumors.