Beyond CAR-T: Engineered NK cell therapies (CAR-NK, NKCEs) in next-generation cancer immunotherapy

Natural killer (NK) cells offer distinct advantages over CAR-T therapies, including reduced toxicity and 'off-the-shelf' potential. This review critically evaluates engineered NK innovations (CAR-NK, cytokine armoring, NKCEs) and their clinical translation, with emphasis on overcoming immunosuppression in solid tumors. We highlight the limitations of CAR-T cells-such as cytokine release syndrome (CRS), neurotoxicity, and antigen escape- and detail how NK cell-based therapies address safety challenges (e.g., reduced CRS/GvHD) and offer 'off-the-shelf' applicability. Notably, antigen escape remains a shared limitation for both platforms. Key innovations in engineered NK cell therapies-including CAR-NK, cytokine armoring (e.g., IL-15), and bispecific/trispecific NK cell engagers (NKCEs)-are critically evaluated. We further address translational barriers, including immunosuppression within the tumor microenvironment (TME), metabolic constraints, and NK cell exhaustion, and discuss strategies to enhance homing, infiltration, and durability. Clinical progress in hematologic malignancies and solid tumors is summarized, emphasizing promising trial outcomes (e.g., 83 % remission in lymphoma with CAR19-NK). Finally, we outline future directions: logic-gated CARs, iPSC-derived NK platforms, and combinatorial approaches with immune checkpoint blockade. CAR-NK therapy represents a paradigm shift in immuno-oncology, augmented by strategies like NKCEs and cytokine armoring. These engineered approaches converge to expand treatment options for refractory cancers.