Natural killer cell membrane manipulation for augmented immune synapse and anticancer efficacy

Abstract

Natural killer (NK) cells are proving a powerful platform in cancer immunotherapy due to their innate cytotoxicity and ability to recognize tumor cells independently of antigen presentation. In preclinical and clinical studies, engineered NK cells expressing chimeric antigen receptors (CARs) have demonstrated strong antitumor efficacy, showcasing the potential of genetic reprogramming to enhance specificity and activation. In parallel, biomaterial-assisted surface engineering has gained momentum as a complementary strategy, offering a genomeindependent and modular means of customizing NK cell functionality. Recent advances in covalent conjugation, metabolic glycoengineering, bio-orthogonal click chemistry, and hydrophobic insertion using biomaterials have facilitated the precise presentation of targeting ligands and immunomodulatory molecules directly onto the NK cell membrane. These strategies support programmable cell-tumor interactions, while maintaining the native cytotoxicity of NK cells. Although several challenges remain, including in vivo persistence and control of effector responses, surface engineering approaches offer practical advantages in flexibility, reversibility, and manufacturing. This review highlights key advances in NK cell-based cancer immunotherapy, with particular focus on: (1) the therapeutic potential and clinical application of native NK cells, (2) the development of CAR-NK cell platforms, and (3) emerging biomaterial-assisted surface engineering strategies to enhance immune synapse. Together, these developments expand the toolkit for NK cell-based therapies and suggest that material-guided engineering may play a valuable role alongside genetic strategies in shaping the next generation of cancer immunotherapy.