NF-κB-mediated cytokine secretion and glutamate metabolic reprogramming converge in breast cancer brain tropism

Brain metastases are an increasingly common and life-threatening complication of breast cancer. Here, we report that breast cancer cells with a propensity for cerebral colonization (BrM cells) display a distinct imbalance in the NF-κB pathway characterized by elevated IKKβ and reduced IKKα levels. This imbalance reduces the levels of the downstream NF-κB modulators IκBα and TAX1BP1, fostering a chronically active pro-inflammatory program. Such BrM cells secrete high concentrations of IL-8 and GRO chemokines, enhancing blood–brain barrier permeability in vitro and triggering astrocyte activation in vivo. In parallel, we observed that the altered NF-κB signaling increases the expression of glutamate transporters EAAT1 and EAAT2, which allows BrM cells to uptake and utilize glutamate, a neurotransmitter readily available in the brain, as a key energy source. Analysis of energy metabolism confirms a pronounced reliance on glutamate for both oxidative phosphorylation and glycolysis, which correlates with an increased migratory and invasive capacity. Importantly, pharmacological inhibition of glutamate import curtails in vitro migratory ability and reduces the formation of brain lesions in a murine model. Our study thus highlights a dual strategy employed by BrM cells, whereby they orchestrate a pro-inflammatory milieu to breach the BBB and simultaneously exploit glutamate metabolism to sustain invasiveness. These findings highlight the inflammatory–metabolic axis as a promising target for therapeutic or preventive strategies against breast cancer progression to the brain.