Signal Transduct Target Ther. 2026 Oct 16. pii: 451. [Epub ahead of print]11(1):
Natural killer (NK) cells have emerged as central players in cancer immunotherapy, progressing from basic discovery to clinically validated platforms over five decades. This review synthesizes the evolving understanding of NK cell biology, including subset heterogeneity, epigenetic regulation, and metabolic control, and, as innovative focal points, intratumoral NK heterogeneity, epigenetic modulation, and intracellular immune checkpoints, forming the foundation for rational therapeutic engineering. We examine the clinical trajectory from unmodified adoptive transfer to cytokine-induced memory-like NK cells and, most transformatively, to chimeric antigen receptor (CAR)-NK cells. Landmark trials have established the remarkable efficacy and superior safety of CAR-NK cells in B-cell malignancies, with recent studies extending these benefits to autoimmune diseases such as systemic lupus erythematosus and systemic sclerosis, demonstrating durable immune reset with a favorable safety profile. Despite these advances, solid tumors remain formidable challenges, hindered by antigen heterogeneity, physical barriers, and a metabolically hostile microenvironment. We therefore analyze next-generation engineering strategies that move beyond single modifications toward systems-level reprogramming, encompassing intrinsic enhancements (cytokine signaling, metabolic fitness, checkpoint disruption), extrinsic tumor microenvironment remodeling, and advanced delivery platforms. We further synthesize the practical dimensions of clinical translation by systematically examining key optimization parameters that will guide the path toward precision NK cell therapy. These include rational dosing and scheduling regimens, strategies to reduce lymphodepletion intensity, context-dependent persistence requirements across different disease indications and the emerging biomarker landscape.