STING-associated metabolic changes engage AMPK to amplify interferon signaling in Listeria-infected macrophages

Innate immune activation is tightly coupled to metabolic remodeling, yet how STING-associated signaling intersects with macrophage metabolism during bacterial infection remains incompletely understood. Here, using Listeria monocytogenes infection models, we show that infection is accompanied by increased glycolytic gene expression, glucose consumption, and lactate production in macrophages, and that STING deficiency attenuates these metabolic changes, whereas cGAS deficiency has a comparatively limited effect under our experimental conditions. Reduced glucose availability, 2-deoxy-d-glucose, and metformin enhanced AMPK activation, TBK1 phosphorylation, and IFN/ISG transcription, whereas Compound C treatment or Prkaa1 knockdown attenuated this enhancement. STING deficiency or acute STING inhibition reduced infection-associated glucose metabolic responses and limited the amplification of type I interferon-response gene expression under metabolic stress. Although the upstream mechanism by which STING regulates glucose metabolism remains to be fully defined, our findings support a model in which STING-associated metabolic changes and AMPK activity cooperate to enhance infection-induced interferon signaling during Listeria monocytogenes infection.