1. A Hybrid Nanoadjuvant Simultaneously Depresses PD-L1/TGF-β1 and Activates cGAS-STING Pathway to Overcome Radio-Immunotherapy Resistance.
- Author
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Yi L, Jiang X, Zhou Z, Xiong W, Xue F, Liu Y, Xu H, Fan B, Li Y, and Shen J
- Subjects
- Humans, B7-H1 Antigen antagonists & inhibitors, Immunotherapy, Manganese Compounds pharmacology, Oxides, Transforming Growth Factor beta1 antagonists & inhibitors, Nucleotidyltransferases drug effects, Membrane Proteins drug effects, Lung Neoplasms radiotherapy, Lung Neoplasms therapy, Neoplasms radiotherapy, Neoplasms therapy, Adjuvants, Pharmaceutic pharmacology, Adjuvants, Pharmaceutic therapeutic use
- 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 Mn
2+ 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., (© 2024 Wiley‐VCH GmbH.)- Published
- 2024
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