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  3. Chemical engineering of γδ T cells with cancer cell-targeting antibodies for enhanced tumor immunotherapy

Chemical engineering of γδ T cells with cancer cell-targeting antibodies for enhanced tumor immunotherapy

  • Natl Sci Rev. 2025 Jun 27;12(8):nwaf256. doi: 10.1093/nsr/nwaf256.
Long Chen 1,  Bo Cheng 2 3 4,  Zhanqun Yang 1,  Mengzhu Zheng 5,  Tianyu Chu 2 3,  Pan Wang 6,  Tianhui He 6,  Yuan Xue 1,  Houyi Ren 1,  Liting Zheng 7,  Peng Zhou 8,  Xiaxuan Li 5,  Haichuan Zhu 9,  Hongyan Guo 6,  Xing Chen 2 3 10 11 12,  Jian Lin 1 5 11 13
Affiliations

Affiliations

  • 1 Department of Pharmacy, Peking University Third Hospital Cancer Center, Peking University Third Hospital, Beijing 100191, China.
  • 2 College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
  • 3 Beijing National Laboratory for Molecular Sciences, Peking University, Beijing 100871, China.
  • 4 School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • 5 Key Laboratory of Tropical Biological Resources of Ministry of Education, Song Li's Academician Workstation of Hainan University, School of Pharmaceutical Sciences, Hainan University, Haikou 572000, China.
  • 6 Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China.
  • 7 Artificial Auditory Laboratory of Jiangsu Province, Xuzhou Medical University, Xuzhou 221004, China.
  • 8 LinXCell Biotechnologies, Beijing 102600, China.
  • 9 School of Life Science and Health, Wuhan University of Science and Technology, Wuhan 430081, China.
  • 10 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
  • 11 Synthetic and Functional Biomolecules Center, Peking University, Beijing 100871, China.
  • 12 Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Peking University, Beijing 100871, China.
  • 13 College of Life Science, Anhui Medical University, Hefei 230032, China.
PMID: 40842867 DOI: 10.1093/nsr/nwaf256
Abstract

Gamma delta (γδ) T cells hold great promise in adoptive cell therapy, but suffer from low tumor-targeting efficiency. Herein, we report the development of antibody-γδ T cell conjugates for enhanced tumor therapy. By evaluating different biomolecules residing on the cell surface, sialic acids-the terminal sugars of various cell-surface glycans-are identified as the optimum site for anchoring antibodies onto γδ T cells via metabolic glycan labeling with unnatural sugars containing a bioorthogonal functional group. A programmed death-ligand 1 (PD-L1)-specific nanobody (αPD-L1) is conjugated onto γδ T cells via click chemistry and the resulting αPD-L1-γδ T cells exhibit enhanced cytotoxicity towards PD-L1-positive Cancer cell lines, patient-derived primary Cancer cells, and xenografted tumors in living mice. Mechanistically, αPD-L1-γδ T cells target Cancer cells and tumors via binding to PD-L1 and induce Cancer cell Pyroptosis. Furthermore, αPD-L1-γδ T cells remodel the tumor microenvironment to be immune-active, at least partially through the recruitment and activation of CD8+ T cells via the CCR5/CCL5 axis. This work provides a versatile strategy for chemical engineering of γδ T cells for improved therapeutic applications.

Keywords

antibody-γδ T cell conjugate; chemical engineering; metabolic glycan labeling; sialic acid; tumor microenvironment.

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