Focused Ultrasound-Induced Mechanical Ablation Affects the Carbohydrate Metabolism of Residual/Peri-Focally Localized...

Glioblastomas (GBMs) are highly aggressive and therapy-resistant brain tumors, mainly driven by stem-like cells and profound metabolic plasticity. Novel treatment strategies, including mechanical high-intensity focused ultrasound (mFUS), are being developed, but their effects on tumor metabolism remain poorly understood. To address this gap, we investigated the impact of mFUS on carbohydrate metabolism in patient-derived GBM organoids and 3D glioma stem-like cell (GSC) cultures. We showed that mFUS selectively induced the expression of glycolysis- and metabolite-transport-associated molecules (GLUT1, HK2, PKM2, LDHA, MCT1, MCT4), particularly in GSCs, as confirmed by qPCR and immunofluorescence. Functional assays demonstrated increased glucose uptake after mFUS, while lactate production remained unchanged. Notably, pharmacological inhibition of GLUT1 or MCT1 potentiated the cytotoxic effects of mFUS, significantly reducing the survival of peri-focal GSCs. Together, these results reveal that mFUS promotes metabolic adaptations in GBM cells and that combined metabolic inhibition may enhance its therapeutic efficacy.