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 genome-independent 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.

Natural killer (NK) cells are promising effectors for cancer immunotherapy, as they can recognize and eliminate tumor cells without prior antigen sensitization. However, insufficient tumor recognition remains a critical limitation that reduces the anticancer efficacy of NK cells against solid tumors. To address this limitation, we developed a lipid-mediated cell membrane engineering strategy to enhance the targeting and cytotoxic efficacy of NK cells toward solid tumors, particularly ovarian cancer cells. In this strategy, poly-L-glutamic acid (PLE) was employed as an ovarian cancer-targeting module due to the specific affinity of PLE for cholesterol-rich membrane domains. To display PLE on NK cells, a lipid moiety is incorporated to anchor PLE onto the NK cell membrane via hydrophobic insertion, enabling rapid and non-genetic surface modification. As a result, the surface-engineered NK cells with PLE-Lipid (i.e., PLE-NK) displayed PLE on the NK cell surface, allowing direct recognition of ovarian cancer cells without compromising the intrinsic properties of NK cells. This enhanced recognition subsequently increased NK–cancer cluster formation by promoting interactions between membrane-presented PLE on NK cells and cholesterol on ovarian cancer cells. Consequently, PLE-NK cells exhibited enhanced cytotoxicity against ovarian cancer cells (i.e., OVCAR-3 cells) and effectively disrupted 3D tumoroids, while PLE-NK cells showed no off-target effects on normal fibroblasts. Collectively, these findings demonstrate that PLE-Lipid-mediated NK surface engineering provides a simple and effective strategy to improve the tumor targeting ability of NK cells and offers a promising platform for NK cell-based immunotherapy against ovarian cancer.