Metabolic-translational control of NK cell fitness under chronic stress

Natural killer (NK) cells are critical mediators of immune surveillance, yet their functional capacity is frequently compromised by chronic metabolic and environmental stress. Although metabolic reprogramming is recognized as a major determinant of NK-cell activity, how metabolic capacity is coordinated with translational control to sustain effector function and cellular persistence remains poorly understood. This review examines NK-cell fitness as a dynamic metabolic-translational balance in which nutrient availability, mitochondrial function, redox homeostasis, and nutrient-sensing pathways determine the resources available for biosynthesis, while translational control regulates their allocation toward effector protein production, adaptation, and cellular maintenance. We highlight eukaryotic elongation factor-2 kinase (eEF2K) as a mechanistically defined regulator of translational elongation with direct evidence of relevance to NK-cell function, while Nucleus Accumbens-Associated Protein 1 (NAC1) is considered a candidate regulator of NK-cell metabolic adaptation whose role remains to be established. We propose that the interaction between metabolic capacity and translational demand may determine whether NK cells maintain function or become dysfunctional under persistent stress. This framework provides a rationale for engineering NK cells with greater metabolic-translational reserve and resilience to metabolically restrictive tumor microenvironments, with potential implications for improving the persistence and therapeutic efficacy of adoptive and CAR-NK cell therapies.