Redirecting Killer T Cells through Incorporation of Azido Sugars for Tethering Ligands

The genetic expression of chimeric antigen receptors (CARs) on the surfaces of T cells enables the redirection of T cell specificity. To enhance the versatility of T cells as tumor‐specific killers, we developed a nongenetic approach by which azide‐containing sialic acids were metabolically incorporated into T cells to modify cellular sialyl glycans. After successful display of these moieties on the T cells, small‐molecule ligands such as RGD and folate (as proof‐of‐concept, rather than supersized antibodies) were clicked orthogonally, leading to highly selective time‐ and dose‐dependent cytotoxicity to integrin α v β 3 ‐ and folate‐receptor‐positive cells, respectively. This chemical approach provides a facile platform for rational design of tumor‐specific cytotoxic T cells for targeted immunotherapy.