In a groundbreaking study published in the journal National Science Review , researchers from Peking University have introduced a novel strategy to enhance the efficacy of γδ T cells in cancer immunotherapy. γδ T cells, a unique subset of T lymphocytes, have shown potential in allogeneic adoptive cell therapy but face limitations due to low tumor-targeting efficiency. To address this, the team developed antibody-γδ T cell conjugates by metabolic labeling of cell-surface glycans with unnatural sugars containing a bioorthogonal functional group, followed by click reaction to conjugate or glue tumor-targeting antibodies.
The researchers identified cell-surface sialic acids as the optimal site for anchoring antibodies onto γδ T cells and further developed a safe, fast and efficient metabolic glycan labeling strategy to construct antibody-γδ T cell conjugates. The proof-of-concept αPD-L1-γδ T cell conjugate showed promising anti-tumor efficacy both in vitro and in vivo towards PD-L1-positive cancers. Mechanistically, the αPD-L1-γδ T cells targeted cancer cells by binding to PD-L1, inducing pyroptosis—a form of programmed cell death. Additionally, these cells remodeled the tumor microenvironment (TME) to be more immune-active, partly through the recruitment and activation of CD8 + T cells via the CCR5-CCL5 axis. This dual action not only enhances the direct killing of cancer cells but also promotes a more favorable TME for sustained anti-tumor immunity. This work offers a novel therapeutic strategy for solid tumors based on γδ T cells.
This work was led by Prof. Jian Lin, Xing Chen, Hongyan Guo and Long Chen from Peking University. The collaborative team is dedicated to developing cutting-edge chemical biology technologies for advancing tumor immuno-therapies.
National Science Review
Experimental study