The metabolic profiles of cancer stem cells.

Cancer stem cells (CSCs) represent a minor but highly adaptable subpopulation within tumors that drives long-term growth, metastasis, and therapy resistance. Their ability to survive and regenerate under metabolic and therapeutic stress relies on a unique integration of energy flexibility, redox balance, and proteostatic programs. While bulk tumor cells typically favor aerobic glycolysis and high protein turnover, CSCs often exhibit elevated mitochondrial activity, fatty acid oxidation, and selective suppression of proteasome function. These metabolic features support quiescence, stress tolerance, and self-renewal. Beyond energy production, metabolic intermediates such as acetyl-CoA, succinate, and lactate serve as epigenetic cofactors, linking nutrient availability to chromatin remodeling and transcriptional plasticity. Reactive oxygen species and antioxidant responses further tune this balance, shaping the transition between glycolytic and oxidative CSC states. These intrinsic programs are continuously influenced by the tumor microenvironment, where hypoxia, cytokine-driven signaling, and metabolic coupling with stromal and immune cells modulate CSC metabolism and reinforce stemness. Despite rapid progress, major conceptual and methodological gaps still limit our understanding of CSC metabolism and this review highlights these unresolved issues and further outline key contextual factors-including tumor-intrinsic, microenvironmental, systemic, and metastatic cues-that shape CSC metabolism and help explain the divergent observations reported across studies. Understanding this network will be essential for designing combinatorial therapies that target CSC metabolism while accounting for their heterogeneity and plasticity.