Glycan Covalent Targeting Chimera‐Based T‐Cell Glycoengineering for Boosting Immunotherapy

Abstract Chimeric antigen receptor (CAR) T‐cell therapy is one of the most effective approaches in cancer immunotherapy. However, shortcomings such as loss of target antigens and poor infiltration remain in the treatment of solid tumors. Herein, we propose an approach to glycoengineer T cells based on glycan covalent targeting chimera (gcTAC), to enhance immunotherapy by modulating the glycan recognition behavior of T cells. We select hydrazide‐modified phenylboronic acid (PBA) as gcTAC. The hydrazide group can covalently couple with the aldehyde group generated by the oxidation of galactose/ N ‐acetylgalactosamine on the surface of T cells, while the PBA at the other end can specifically bind to sialic acids (Sia) of tumor cells, thereby enhancing the killing effect of T cells. At the same time, T cells covalently bound to tumor cells surfaces act as a blockade of Sia sites, which can disrupt the recognition between Siglec on natural killer (NK) cells and Sia on tumor cells, further enhancing the immune‐killing effect of combined T–NK cell therapy. Our approach represents a novel concept to promote immune killing through cascading interventions in T–tumor and tumor–NK intercellular glycan recognition, thus providing a solution to the problem of immune escape in cancer therapy.