Lipid metabolism in cancer stem cells: reprogramming, mechanisms, crosstalk, and therapeutic approaches

Cancer stem cells (CSCs) are a highly plastic subpopulation of tumor cells with capabilities for self-renewal, therapy resistance, and metastasis. Recent evidence highlights lipid metabolic reprogramming as a central mechanism supporting these malignant traits. This review synthesizes current findings on key lipid metabolic processes in CSCs-including lipid uptake via CD36, intracellular storage in lipid droplets, de novo fatty acid synthesis by fatty acid synthase (FASN), fatty acid oxidation (FAO) regulated by carnitine palmitoyltransferase 1A (CPT1A), and cholesterol biosynthesis through the mevalonate pathway. Although many of these pathways are active in bulk cancer cells, CSCs demonstrate greater functional reliance on them, leading to enhanced survival, redox balance, and adaptation to therapy. These metabolic preferences vary by cancer type, underscoring the need for context-specific approaches. Moreover, stromal components of the tumor microenvironment (TME), such as cancer-associated fibroblasts, adipocytes, and mesenchymal stem cells, modulate CSC lipid metabolism through paracrine signals and substrate transfer, reinforcing CSC maintenance and drug resistance. Therapeutic strategies targeting lipid metabolism-such as inhibition of SCD1, CPT1A, and HMG-CoA reductase-have shown promising preclinical results in selectively depleting CSC populations and sensitizing tumors to treatment. However, challenges remain in preserving normal stem cell function, which also depends on lipid pathways. This review underscores the emerging significance of lipid metabolism as both a hallmark and vulnerability of CSCs, offering opportunities for novel targeted cancer therapies.