Metabolic reprogramming of NK cells drives anti-tumor immunity.

Cellular metabolism critically controls immune cell functionality, necessitating dynamic metabolic adaptation to sustain effector responses under microenvironmental fluctuations. Natural killer (NK) cells, innate lymphocytes essential for tumor immunosurveillance, exhibit functional plasticity intrinsically linked to metabolic reprogramming. While NK cell-based immunotherapy show promise due to MHC-independent cytotoxic, their clinical efficacy diverges markedly between hematological and solid tumor-a disparity rooted in tumor microenvironment (TME) driven immunosuppression. Cancer cells subvert NK cell elimination through metabolic competition, creating nutrient-depleted milieus that impair mitochondrial bioenergetics and glycolytic flux in tumor-infiltrating NK populations. These constraints induce functional exhaustion, characterized by diminished cytokine production and cytotoxic granule release, facilitating immune evasion. Emerging strategies targeting metabolic checkpoints-including glucose utilization, amino acid metabolism, and lipid signaling-demonstrate capacity to restore NK cell metabolic fitness. Preclinical models reveal enhanced anti-tumor activity when combining metabolic modulators with cytokine priming or checkpoint inhibitors, establishing metabolic optimization as a biochemical framework to overcome TME limitations. These advances position NK cell metabolic engineering as a promising approach for next-generation solid tumor immunotherapies, driving translational research toward precision metabolic reprogramming strategies.