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

Abstract 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.