%0 Journal Article
%T A Hybrid Nanoadjuvant Simultaneously Depresses PD-L1/TGF-β1 and Activates cGAS-STING Pathway to Overcome Radio-Immunotherapy Resistance.
%A Yi L
%A Jiang X
%A Zhou Z
%A Xiong W
%A Xue F
%A Liu Y
%A Xu H
%A Fan B
%A Li Y
%A Shen J
%J Adv Mater
%V 36
%N 15
%D 2024 Apr 17
%M 38229577
%F 32.086
%R 10.1002/adma.202304328
%X 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.