Concurrent Amplification of Ferroptosis and Immune System Activation Via Nanomedicine‐Mediated Radiosensitization for Triple‐Negative Breast Cancer Therapy

Radiation therapy (RT) is one of the core therapies for current cancer management. However, the emergence of radioresistance has become a major cause of radiotherapy failure and disease progression. Therefore, overcoming radioresistance to achieve highly effective treatment for refractory tumors is significant yet challenging. Here, pH-responsive DSPE-PEoz modified hollow Bi₂Se₃-RSL3/diABZi (DP-HBN/RA) nanomedicine is designed as a radiation sensitizer for efficient treatment of triple-negative breast cancer by simultaneously amplifying ferroptosis and immune system activation. DP-HBN/RA can efficiently concentrate X-ray radiation energy inside the tumor, thereby promoting precise ionizing radiation exposure in tumor cells to produce large amounts of reactive oxygen species (ROS), leading to lipid peroxidation-induced ferroptosis. Meanwhile, ferroptotic cell death is intensified through the inactivation of GPX4 by RSL3 released from DP-HBN/RA to acidic conditions in the tumor microenvironment. Additionally, DP-HBN/RA enhances RT efficacy to exacerbate unrepairable DNA damage and release DNA fragments that activate the cGAS-STING signal pathway, evoking a systematic immune response. Ingeniously, the released diABZi reinforces cGAS-STING activation to boost the immunology antitumor effect. This work links the induction of ferroptosis and the initiation of systematic immune response to achieve highly effective tumor suppression, which opens up new avenues for future treatments of refractory tumors.