Metabolic Reprogramming of Cancer Stem Cells: Targeting Lipid Flux and Mitochondrial Plasticity to Overcome Therapeutic Resistance.

Cancer stem cells (CSCs) are increasingly recognized as metabolically plastic subpopulations within malignant tissues that drive tumor initiation, metastatic dissemination, and relapse after therapy. Although traditional models of cancer metabolism have emphasized aerobic glycolysis, CSCs rarely exhibit a single, clearly defined bioenergetic phenotype. Rather, they dynamically remodel glucose utilization, oxidative phosphorylation, redox regulation, de novo fatty acid synthesis, lipid uptake, lipid sequestration, and fatty acid oxidation in response to hypoxic conditions, nutrient restriction, stromal interactions, and therapeutic perturbations. This review focuses on two interconnected aspects of metabolic flexibility: lipid flux and mitochondrial plasticity. We examine how de novo lipogenesis, CD36-mediated fatty acid uptake, fatty acid-binding protein trafficking, cholesterol biosynthesis, and lipid-droplet turnover contribute to stemness, membrane remodeling, metastatic potential, and resistance to cytotoxic agents. We also examine how mitochondrial dynamics, including fusion, fission, mitophagy, and biogenesis, together with reactive oxygen species buffering and shifts in oxidative phosphorylation, facilitate CSC survival during chemotherapy, radiotherapy, targeted therapy, and immune-mediated cytotoxicity. Particular emphasis is placed on the integration of fatty acid oxidation to respiratory metabolism, on the epigenetic consequences associated with the acetyl-CoA availability, and the metabolic crosstalk linking CSCs to adipocytes, fibroblasts, mesenchymal cells, and immune cell populations in the tumor microenvironment. Finally, we evaluate therapeutic strategies involving inhibitors of fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), stearoyl-CoA desaturase-1 (SCD1), carnitine palmitoyltransferase-1 (CPT1), and OXPHOS. We also discuss combination therapies, nanotechnology-based drug delivery, and emerging artificial intelligence (AI)-guided approaches. Taken together, current evidence identifies the lipid-mitochondrial axis as a critical systems-level driver of therapeutic resistance and a promising target for improving long-term cancer control.