T Cell Glycoengineering to Modulate Immune‐Tumor Crosstalk: A Universal Non‐Genetic Strategy for Enhanced Tumor Immunotherapy

Gene-engineered T cell therapies, particularly chimeric antigen receptor (CAR)-T cells, have demonstrated remarkable clinical success. However, concerns regarding insertional mutagenesis and other risks associated with genetic modification remain. Here, a non-genetic strategy is presented for T cell engineering using glycopolymer modification. It develops glycopolymer-modified T (G-T) cells based on antigen-specific T cells by integrating metabolic glycoengineering and click chemistry, yielding cells that retain T cell functionality while significantly enhancing tumor enrichment. The polyvalent glycopolymer-receptor interactions significantly improved the binding affinity of G-T cells to various glucose transporter 1 (GLUT1)-overexpressing tumor cells, resulting in increased cytotoxicity compared to unmodified T cells. In the tumor microenvironment, G-T cells engaged in stronger immune crosstalk with dendritic cells (DCs), upregulating interferon-gamma (IFN-γ) and interleukin-12 (IL-12) secretion and amplifying the anti-tumor immune response. Notably, despite the lower specificity of glycan-receptor interactions compared to antigen-antibody binding, the findings reveal an unexpected advantage: the "less restrictive" nature of glycan-receptor recognition enhances both tumor and immune cell interactions, triggering a potent immune cascade. This study establishes a universal, non-genetic T cell engineering strategy with broad applicability, offering a new perspective for tumor immunotherapy by merging biomedical polymer materials with immune modulation.