Targeting metabolic reprogramming in persister cancer cells: Emerging insights and therapeutic opportunities

ABSTRACT: Persister cancer cells (PCCs) constitute a transient tumor subpopulation that survives anticancer therapy by entering a drug-tolerant state, characterized by enhanced stress resilience and profound metabolic adaptation. Unlike genetically resistant clones, PCCs rely on reversible metabolic adaptations centrally coordinated by mitochondria. This coordination enables a context-dependent metabolic switch between glycolysis and oxidative phosphorylation, augmented fatty acid oxidation, rewired amino acid metabolism, and autophagy-mediated nutrient recycling. Collectively, these adaptations maintain energy and redox homeostasis, allowing PCCs to evade apoptosis and ferroptosis. Critically, these unique metabolic features represent therapeutically exploitable vulnerabilities that can be targeted before the emergence of stable genetic resistance. This review systematically delineates the metabolic plasticity of PCCs across malignancies, emphasizing the role of mitochondria as an integration hub. Furthermore, we discuss emerging strategies to exploit these vulnerabilities, providing a conceptual framework to prevent acquired resistance by targeting metabolic persistence.