2. Academic Validation
  3. Tumor-specific delivery of clickable inhibitor for PD-L1 degradation and mitigating resistance of radioimmunotherapy

Tumor-specific delivery of clickable inhibitor for PD-L1 degradation and mitigating resistance of radioimmunotherapy

  • Sci Adv. 2024 Nov 15;10(46):eadq3940. doi: 10.1126/sciadv.adq3940.
Bo Hou 1 2 3,  Jiayi Ye 2 4,  Lujia Huang 2 4,  Wenhao Cheng 2,  Fangmin Chen 2 4,  Huiling Zhou 1 2,  Jiaxing Pan 2,  Jing Gao 2,  Yi Lai 2,  Yujun Zhao 5,  Wei Huang 6,  Haijun Yu 2 3 4,  Zhiai Xu 1
Affiliations

Affiliations

  • 1 School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China.
  • 2 State Key Laboratory of Chemical Biology and Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong 264000, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 6 Center for Biotherapeutics Discovery Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
PMID: 39546592 DOI: 10.1126/sciadv.adq3940
Abstract

Achieving selective and durable inhibition of programmed death ligand 1 (PD-L1) in tumors for T cell activation remains a major challenge in Immune Checkpoint blockade therapy. We herein presented a set of clickable inhibitors for spatially confined PD-L1 degradation and radioimmunotherapy of Cancer. Using metabolic glycan engineering click bioorthogonal chemistry, PD-L1 expressed on tumor cell membranes was labeled with highly active azide groups. This enables covalently binding of the clickable inhibitor with PD-L1 and subsequent PD-L1 degradation. A pH-activatable nanoparticle responding to extracellular acidic pH of tumor was subsequently used to deliver the clickable PD-L1 inhibitor into extracellular tumor microenvironment for depleting PD-L1 on the surface of tumor cell and macrophage membranes in vivo. We further demonstrated that a combination of the clickable PD-L1 inhibitor with radiotherapy (RT) eradicated the established tumor by inhibiting RT-up-regulated PD-L1 in the tumor tissue. Therefore, selective PD-L1 blockade in tumors via the clickable PD-L1 inhibitor offers a versatile approach to promote Cancer Immunotherapy.

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