A Hybrid Nanoadjuvant Simultaneously Depress PD-L1/TGF-β1 And Activate Cgas-STING Pathway to Overcome Radio-immunotherapy Resistance.

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 limited their effectiveness. Therefore, we developed a nanoadjuvant to sensitize cancer to radiotherapy via multi-level immunity activation through depressing PD-L1 and TGF-β1 by Triphenylphosphine-derived Metformin (Tpp-Met), and activating the cGAS-STING pathway by generating Mn 2+ from MnO 2 and producing more dsDNA via reversing tumor hypoxia and impairing DDR. Thus, Tpp-Met@MnO 2 @Alb effectively enhanced 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@MnO 2 @Alb had the potential to be clinically applied for overcoming radio-immunotherapy resistance. This article is protected by copyright. All rights reserved.