Immunoregulatory Engineering of Semiconducting Charge‐Reversal Nanoantioxidant for Ameliorating Cancer Radioimmunotheranostics

Abstract Radiotherapy (RT) is a crucial clinical modality for cancer. However, nonselectivity, toxicity to normal tissues, and radio‐resistance severely limit RT applications. This study develops a versatile X‐ray theranostic nano‐antioxidant (XTN) to prevent normal tissues from oxidative damage and induce systematic and robust anticancer immunity. XTN owns NIR‐II photoacoustic (PA) imaging properties for precise discrimination of the tumor margin through, thereby improving the accuracy of RT. Additionally, XTN is a nano‐antioxidant to enhance the cell viability of normal cells after irradiation. Most importantly, XTN scavenges reactive oxygen species (ROS) in the TME to preserve the stimulatory activity of released high mobility group protein B1 to dendritic cells (DCs) and recover T cells’ immune function. Meanwhile, XTN achieves charge‐reversal specifically releasing an immunomodulator (demethylcantharidin, DMC) in the acidic TME. Moreover, the specifically released DMC inhibits protein phosphatase‐2A activity and reduces regulatory T cell (Treg) differentiation. In the bilateral 4T1 tumor model, XTN‐mediated radioimmunotherapy remarkably boosts a systemic antitumor immune response and induces durable immunological memory against tumor growth.