2. Academic Validation
  3. A Hybrid Nanoadjuvant Simultaneously Depresses PD-L1/TGF-β1 and Activates cGAS-STING Pathway to Overcome Radio-Immunotherapy Resistance

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

  • Adv Mater. 2024 Jan 17:e2304328. doi: 10.1002/adma.202304328.
Lei Yi 1 2,  Xin Jiang 3,  Zaigang Zhou 2,  Wei Xiong 4,  Fei Xue 5,  Yu Liu 2,  Haozhe Xu 1,  Bo Fan 3,  Yuan Li 1,  Jianliang Shen 2 6
Affiliations

Affiliations

  • 1 Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
  • 2 National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
  • 3 Department of Urology, Xiangya Hospital, Central South University, Changsha, 410008, China.
  • 4 Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
  • 5 Department of Radiotherapy, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 6 Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, 325001, China.
PMID: 38229577 DOI: 10.1002/adma.202304328
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.

Keywords

PD-L1/TGF-β1; cGAS-STING; hypoxia reversion; nanoadjuvant; radio-immunotherapy.

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