• CSCs exhibit metabolic plasticity, shifting between glycolytic and oxidative states to support quiescence and stress tolerance.
• Metabolic intermediates like acetyl-CoA and lactate act as epigenetic cofactors, linking nutrient availability to chromatin remodeling and transcriptional plasticity.
• The tumor microenvironment, including hypoxia and stromal/immune cell coupling, modulates CSC metabolism and reinforces stemness.
• Targeting CSC metabolism requires combinatorial strategies that account for heterogeneity and plasticity.