Chen Long, Cheng Bo, Yang Zhanqun, Zheng Mengzhu, Chu Tianyu, Wang Pan, He Tianhui, Xue Yuan, Ren Houyi, Zheng Liting, Zhou Peng, Li Xiaxuan, Zhu Haichuan, Guo Hongyan, Chen Xing, Lin Jian
Department of Pharmacy, Peking University Third Hospital Cancer Center, Peking University Third Hospital, Beijing 100191, China.
College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
Natl Sci Rev. 2025 Jun 27;12(8):nwaf256. doi: 10.1093/nsr/nwaf256. eCollection 2025 Aug.
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.
γδ T细胞在过继性细胞疗法中具有巨大潜力，但肿瘤靶向效率较低。在此，我们报告了用于增强肿瘤治疗的抗体-γδ T细胞偶联物的开发。通过评估细胞表面存在的不同生物分子，唾液酸——各种细胞表面聚糖的末端糖——被确定为通过用含有生物正交官能团的非天然糖进行代谢聚糖标记将抗体锚定到γδ T细胞上的最佳位点。一种程序性死亡配体1（PD-L1）特异性纳米抗体（αPD-L1）通过点击化学偶联到γδ T细胞上，所得的αPD-L1-γδ T细胞对PD-L1阳性癌细胞系、患者来源的原发性癌细胞以及活体小鼠中的异种移植肿瘤表现出增强的细胞毒性。从机制上讲，αPD-L1-γδ T细胞通过与PD-L1结合靶向癌细胞和肿瘤，并诱导癌细胞焦亡。此外，αPD-L1-γδ T细胞将肿瘤微环境重塑为免疫活性状态，至少部分是通过CCR5/CCL5轴招募和激活CD8 T细胞实现的。这项工作为γδ T细胞的化学工程提供了一种通用策略，以改善治疗应用。
