文章：

γδ T细胞靶向癌细胞的抗体化学工程用于增强肿瘤免疫治疗

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

原文发布日期：2025-06-27

DOI: 10.1093/nsr/nwaf256

类型: Journal Article

开放获取: 是

英文摘要：

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.

摘要翻译： 

γδ T细胞在过继细胞治疗中展现出巨大潜力，但其肿瘤靶向效率较低。本研究报道了抗体-γδ T细胞偶联物的开发，以增强肿瘤治疗效果。通过评估细胞表面不同的生物分子，我们发现唾液酸——多种细胞表面聚糖的末端糖基——是通过含生物正交官能团的非天然糖进行代谢聚糖标记后，将抗体锚定于γδ T细胞的最佳位点。利用点击化学将程序性死亡配体1（PD-L1）特异性纳米抗体（αPD-L1）偶联至γδ T细胞，所得的αPD-L1-γδ T细胞对PD-L1阳性癌细胞系、患者来源的原代癌细胞及活体小鼠移植瘤均表现出增强的细胞毒性。机制上，αPD-L1-γδ T细胞通过结合PD-L1靶向癌细胞及肿瘤，并诱导癌细胞发生焦亡。此外，αPD-L1-γδ T细胞能重塑肿瘤微环境为免疫活化状态，至少部分通过CCR5/CCL5轴招募并激活CD8+ T细胞实现。本研究为γδ T细胞的化学工程化提供了通用策略，以提升其治疗应用潜力。

原文链接：

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