癌症研究
免疫疗法
背向效应
放射治疗
医学
免疫系统
免疫学
内科学
作者
Yi Lee,Xin Jiang,Zaigang Zhou,Xiong Wang,Fei Xue,Yu Liu,Haozhe Xu,Bo Fan,Yuan Li,Jianliang Shen
标识
DOI:10.1002/adma.202304328
摘要
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.
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