Glutaminolysis inhibition boosts cuproptosis to eliminate breast cancer stem cells

The metabolic plasticity of cancer stem cells (CSCs) enables them to adaptively switch between glycolysis, oxidative phosphorylation, and alternative fuels such as glutamine and fatty acids, promoting tumorigenesis and progression by ensuring survival under diverse environmental stresses. However, current therapeutic approaches targeting CSCs remain limited, particularly those relying on single metabolic interventions. By leveraging concurrent metabolic modulation and redox disruption to sensitize CSCs to cuproptosis, we prepared a polydopamine/hydroxyethyl starch-based nanoplatform (CH@PHF) for co-delivering copper-diethyldithiocarbamate (CuET) and HYL001. Specifically, HYL001 suppresses glutaminase (GLS) activity, thereby blocking glutamine metabolism and inhibiting glutathione (GSH) biosynthesis. This effect synergizes with CuET to collectively amplify oxidative stress in CSCs. Furthermore, the combination of HYL001 and CuET significantly elevates intracellular copper levels, particularly the cuprous form (Cu + ), thereby sensitizing CSCs to cuproptosis. This combined treatment effectively inhibits tumor growth and metastasis by targeting and eradicating breast cancer stem cells (BCSCs), offering a promising avenue for tumor therapy.