Lipid anchor-mediated NK cell surface engineering for enhanced cancer immunotherapy

Current natural killer (NK) cell-based cancer immunotherapy for the treatment of solid tumors often exhibits insufficient cancer recognition specificity, thereby limiting therapeutic anticancer efficacy, especially for triple-negative breast cancers (TNBCs). In this study, we develop artificial lipid-folate conjugates, for stable anchoring onto NK cell surfaces via hydrophobic interactions, thus augmenting folate-mediated ligand-receptor immune interactions with target cancers. This hydrophobized conjugate anchor provides additional cancer recognition ligands without any sophisticated genetic modification, and successfully enhances the anticancer efficacies of surface-coated NK (SCNK) cells without disturbing their intrinsic properties. Augmented cancer recognition ability sequentially promotes the secretion of cytolytic granules (granzyme and perforin) with cytokine (TNF-α), demonstrating improved cytotoxicity of the SCNK cells. Furthermore, the SCNK cells significantly infiltrate into the tumor site, inducing tumor apoptosis/necrosis, and suppressing tumor progression and metastasis in TNBC mouse models. Taken together, our artificial lipid-folate conjugates enable the treatment of solid tumors by augmenting the cancer-recognition and tumor targeting capacity of surface-engineered NK cells.