Chemical engineering of γδ T cells with cancer cell-targeting antibodies for enhanced tumor immunotherapy
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<sup>+</sup> T cells via the CCR5/CCL5 axis. This work provides a versatile strategy for chemical engineering of γδ T cells for improved therapeutic applications.
Authors
- T W Chu (ORCID: https://orcid.org/0009-0002-2904-7323)
- Haichuan Zhu (ORCID: https://orcid.org/0000-0002-4232-835X)
- Tianhui He (ORCID: https://orcid.org/0000-0002-2835-0702)
- Xiaxuan Li
- Zhanqun Yang
- Hongyan Guo (ORCID: https://orcid.org/0000-0001-6917-5341)
- Mengzhu Zheng
- He Ren (ORCID: https://orcid.org/0000-0002-9528-0580)
- Long Chen (ORCID: https://orcid.org/0000-0002-4055-7108)
- Bo Cheng
- Xing Chen (ORCID: https://orcid.org/0000-0002-3058-7370)
- Pan Wang (ORCID: https://orcid.org/0000-0001-7340-5082)
- Jianhua Lin (ORCID: https://orcid.org/0000-0003-0698-0292)
- Peng Zhou (ORCID: https://orcid.org/0009-0005-4222-4760)
- Yuan Xue (ORCID: https://orcid.org/0000-0002-7457-714X)
- Liting Zheng
Institutions
- Xuzhou Medical College (CN)
- Wuhan University of Technology (CN)
- Anhui Medical University (CN)
- Peking University (CN)
- Hainan University (CN)
- King Center (US)
- Ministry of Education (RO)
- Cell Biotech (South Korea) (KR)
- OPX Biotechnologies (United States) (US)
- Beijing National Laboratory for Molecular Sciences (CN)
- Peking University Third Hospital (CN)
- Center for Life Sciences (CN)
- Wuhan University of Science and Technology (CN)
- Hainan Medical University (CN)
Publication Details
- Journal
- National Science Review
- Published
- 2025-06-27
- DOI
- https://doi.org/10.1093/nsr/nwaf256
- Citations
- 8
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 6.38
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Chongqing
- Peking University
- Centre Scientifique et Technique du Bâtiment