Metabolic Reprogramming in Cancer Stem Cells

Cancer stem cells (CSCs) are a subset of tumor cells that exhibit self-renewal, differentiation potential, and resistance to conventional therapies. One of the characteristic traits of CSCs is their metabolic flexibility, with the ability to adapt energy production and biosynthesis in the context of low oxygen, limited nutrients, and therapy-driven stress. This adaptability allows them to survive, advances tumor development, and results in relapse after treatment.CSCs can switch between glycolysis and oxidative phosphorylation (OXPHOS) dynamically in different biological contexts. CSCs mainly produce ATP and synthesize nucleotides, amino acids, and lipids through glycolysis in hypoxia. OXPHOS is important for the maintenance of quiescent cells, for reducing reactive oxygen species (ROS) production, and supports long-term survival and tumor initiation. In addition to glucose, CSCs utilize lipid and amino acid metabolism. Fatty acid oxidation provides energy during stress, while glutamine, serine, and glycine support biosynthesis, redox homeostasis, and epigenetic control, collectively enhancing survival and therapy resistance. CSCs also rely on lipid and amino acid metabolism, in addition to glucose. Fatty acid oxidation is a source of energy during stress, and glutamine-, serine-, and glycine-derived metabolic products contribute to promoting biosynthesis for redox homeostasis, epigenetic regulation, and survival/therapy resistance. The tumor microenvironment (TME) dictates CSCs' metabolism through cross talk with fibroblasts, immune cells, and components of the extracellular matrix. Metabolic interplay, e.g., reverse Warburg effect, allows CSC to consume stromal metabolites, facilitating the promotion of tumor and resistance to therapy. Targeting of CSC metabolism, via glycolytic and mitochondrial inhibitors, lipid metabolism originated blockers, or amino acids modulators can perturb the survival of CSCs and increase tumor sensitivity to classical therapies. In this aspect, the application of combinatorial therapy was able to provide additional benefit by addressing both proliferative and quiescent CSC.In conclusion, metabolic reprogramming underpins CSC survival, drives therapy resistance, and promotes tumor progression. Exploiting these metabolic adaptations provides a promising strategy for achieving long-lasting and effective cancer therapies.