Eliminating Radioresistance With a Magnetic Ion‐Generator by Simultaneously Augmenting DNA Damage and Diminishing Immunosuppression

Radiotherapy (RT) hinges on DNA damage-induced cancer cell death and the subsequent anti-tumor immunity. However, the efficacy of RT is curtailed by cell cycle heterogeneity and an immunosuppressive tumor microenvironment, which foster radioresistance. Here an ion generator-based RT enhancement strategy is demonstrated in a mouse model of the radioresistant tumor. The ion generator is degraded in the tumor microenvironment, resulting in iron-triggered ferroptosis that enhanced immunogenic cell death and a manganese-activated stimulator of interferon gene that reversed the immunosuppressive environment. As a result, the proposed strategy promotes dendritic cells maturity, augmentes CD8+ T cell infiltration of tumors, suppresses intratumoral myeloid-derived suppressor cells, and limits the M2 macrophages polarization, indicating the formation of an immunoreactive microenvironment. Significantly, this approach impedes the growth of not just primary, but also distal metastatic tumors. It is thus believed that the current ion generator provides a robust and enduring countermeasure to radioresistant cancer and its metastasis, with potential implications for enhancing the efficacy of RT in clinically resistant tumors.