Click Chemistry‐Mediated Polymannose Surface‐Engineering of Natural Killer Cells for Immunotherapy of Triple‐Negative Breast Cancer

Abstract Natural killer (NK) cells, serve as the frontline defense of the immune system, and are capable of surveilling and eliminating tumor cells. Their significance in tumor immunotherapy has garnered considerable attention in recent years. However, the absence of specific receptor–ligand interactions between NK cells and tumor cells hampers their selectivity, thereby limiting the therapeutic effectiveness of NK cell‐based tumor immunotherapy. Herein, this work constructs polymannose‐engineered NK (pM‐NK) cells via metabolic glycoengineering and copper‐free click chemistry. Polymannose containing dibenzocyclooctyne terminal groups (pM‐DBCO) is synthesized and covalently modified on the surface of azido‐labeled NK cells. Compared to the untreated NK cells, the interactions between pM‐NK cells and MDA‐MB‐231 cells, a breast tumor cell line with overexpression of mannose receptors (MRs), are significantly increased, and lead to significantly enhanced killing efficacy. Consequently, intravenous administration of pM‐NK cells will effectively inhibit the tumor growth and will prolong the survival of mice bearing MDA‐MB‐231 tumors. Thus, this work presents a novel strategy for tumor‐targeting NK cell‐based tumor immunotherapy.