A Hybrid Nanoadjuvant Simultaneously Depresses PD‐L1/TGF‐β1 and Activates cGAS‐STING Pathway to Overcome Radio‐Immunotherapy Resistance

Abstract Currently, certain cancer patients exhibit resistance to radiotherapy due to reduced DNA damage under hypoxic conditions and acquired immune tolerance triggered by transforming growth factor‐β1 (TGF‐β1) and membrane‐localized programmed death ligand‐1 (PD‐L1). Meanwhile, cytoplasm‐distributed PD‐L1 induces radiotherapy resistance through accelerating DNA damage repair (DDR). However, the disability of clinically used PD‐L1 antibodies in inhibiting cytoplasm‐distributed PD‐L1 limits their effectiveness. Therefore, a nanoadjuvant is developed to sensitize cancer to radiotherapy via multi‐level immunity activation through depressing PD‐L1 and TGF‐β1 by triphenylphosphine‐derived metformin, and activating the cGAS‐STING pathway by generating Mn²⁺ from MnO₂ and producing more dsDNA via reversing tumor hypoxia and impairing DDR. Thus, Tpp‐Met@MnO₂@Alb effectively enhances the efficiency of radiotherapy to inhibit the progression of irradiated local and abscopal tumors and tumor lung metastases, offering a long‐term memory of antitumor immunity without discernible side effects. Overall, Tpp‐Met@MnO₂@Alb has the potential to be clinically applied for overcoming radio‐immunotherapy resistance.