T-Cell Surface Engineering for Enhanced Antitumor Immunotherapy Using Metabolic Click Chemistry

T cells play a crucial role in immune therapy for various cancer treatments, which are capable of recognizing and eliminating tumor cells. However, antigen loss and suppressive tumor microenvironments (TME) lead to impaired T-cell antitumor immunity. Here, we describe a strategy of T-cell surface engineering for enhanced immune therapy using metabolic click chemistry. Immune checkpoint inhibitor (ICIs) conjugation and artificial targeting on the T-cell surface are performed through a specific click reaction based on cell glycometabolic modification. This approach boosts T/CAR-T cell infiltration, cytokine secretion (e.g., TNF-α, IFN-γ), and cytotoxicity, thus achieving 65% greater tumor suppression in comparison to conventional CAR-T therapy in vivo. Furthermore, conjugating anti-PD-L1 antibodies onto CAR-T cells (anti-PD-L1-CAR-T) synergistically enhances the antitumor efficacy by blocking PD-1/PD-L1 immunosuppression. In murine models, anti-PD-L1-CAR-T achieved 100% survival and promoted intratumoral CD8+ T cell persistence (Ki67+/IFN-γ+). These findings provide an innovative T cell engineering strategy for enhanced antitumor therapy with a significant clinical potential.