Abstract Natural killer (NK) cells are the primary innate lymphoid cells responsible for antiviral defense and tumor immunosurveillance. However, further clarification is needed on how to prevent their over-activation and maintain their quiescence during development. In this study, we present evidence that liver kinase B1 (Lkb1) functions as a critical metabolic checkpoint, regulating NK cell survival and preserving their effective tumor immunosurveillance capabilities. Genetic ablation of Lkb1 led to mitochondrial dysfunction and impaired autophagy, resulting in reactive oxygen species (ROS)-dependent cell death. Additionally, Lkb1 deficiency disrupted iron homeostasis, causing iron overload and the subsequent accumulation of cytotoxic lipid ROS. Targeted interventions aimed at inhibiting ROS accumulation or iron overload significantly rescued the survival defect in Lkb1-deficient NK cells. Notably, these regulatory functions could not be rescued by pharmacologic AMPK activation or mTORC1 inhibition. Furthermore, the deletion of Lkb1 increased the expression of inhibitory receptors PD-1 and TIGIT, further impairing NK cell-mediated tumor surveillance. Our investigation collectively highlights the critical role of Lkb1 in maintaining NK cell quiescence through the coordinated regulation of metabolic fitness and redox balance, offering new insights into the metabolic programming of NK cell development and function.
Meng et al. (Fri,) studied this question.