Metabolic and Proteostatic Plasticity of Cancer Stem Cells: Integrating Energy Flexibility, Redox Balance, and Epigenetic Remodeling in Tumor Progression and Therapy Resistance

• • CSCs exhibit elevated mitochondrial activity and fatty acid oxidation, contrasting with bulk tumor glycolysis, supporting quiescence and stress tolerance; this metabolic flexibility is a target for differentiation therapy. • • Selective suppression of proteasome function in CSCs, as evidenced by hypersensitivity to proteasomal inhibition in glioma-derived CSCs (Yoo et al., EMBO Rep 2017), suggests proteasome inhibitors could selectively eradicate CSCs. • • Metabolic intermediates (acetyl-CoA, succinate, lactate) act as epigenetic cofactors, linking nutrient availability to chromatin remodeling and transcriptional plasticity, offering targets for epigenetic drugs. • • The tumor microenvironment, including hypoxia and cytokine signaling, modulates CSC metabolism and reinforces stemness, implying that anti-stromal therapies may disrupt CSC maintenance.