Dendritic cell–natural killer (DC–NK) metabolic checkpoint conceptually links DC metabolic state, governed by autophagy and AMPK/mTOR signaling, to NK cell antiviral effector readiness in viral asthma exacerbations. In several asthma endotypes (type 2-high, type 2-low, obesity-related), chronic hypoxia, HIF-1α stabilization, ORMDL3–ceramide signaling, and systemic metabolic stress drive DCs toward a highly glycolytic, Th2/Th17-polarizing phenotype within a lactate-rich, acidic airway microenvironment.
These metabolically reprogrammed DCs are proposed to modulate NK cell metabolism via three interrelated axes: cytokine-mediated metabolic licensing (IL-12, IL-15, IL-18), exosome-delivered activating versus suppressive cargo, and intense perisynaptic nutrient competition that depletes glucose while lactate accumulation and acidosis further impair NK cell function. The net effect is a dual hit: NK cells become metabolically exhausted and IFN-γ–deficient, despite intact cytotoxic machinery, compromising clearance of virally infected targets.
While much evidence stems from murine and in vitro systems, human metabolomic, genetic, and functional data align with this framework. Therapeutic targeting of autophagic plasticity, AMPK/mTOR balance, or airway nutrient/pH normalization could be explored to prevent viral-triggered asthma exacerbations, pending human validation.