Cancer dormancy and metabolism: From molecular insights to translational opportunities

Cancer dormancy refers to a reversible state where cancer cells enter a quiescent phase, allowing them to evade therapeutic interventions and remain undetected. This state can lead to potential reactivation years later, resulting in relapse and metastasis. This phenomenon presents a significant challenge in cancer treatment, as dormant cells often exhibit resistance to conventional therapies. Recent studies emphasize the crucial role of metabolic reprogramming in regulating cancer dormancy, closely interacting with the tumor microenvironment. Dormant cancer cells undergo metabolic adaptations that enable their survival in a hostile tumor microenvironment. These adaptations include a decreased reliance on glycolysis and an increased dependence on oxidative phosphorylation and fatty acid oxidation. Exosomes, extracellular matrix, and cancer-associated fibroblasts dynamically regulate these metabolic states by mediating intercellular communication and modulating the biochemical and mechanical properties of the tumor microenvironment. In parallel, epigenetic regulation fine-tunes metabolic gene expression, reinforcing the dormant phenotype and enabling plastic transitions between dormancy and proliferation. Additionally, these cells utilize autophagy to recover nutrients and manage microenvironmental stress. These metabolic changes help dormant cells maintain a low metabolic state while preserving their ability to reactivate when conditions become favorable. Understanding the relationship between dormancy and metabolism offers new therapeutic opportunities aimed at targeting metabolic pathways to prevent relapse and metastasis. This review explores the mechanisms of metabolic reprogramming in dormancy induction, maintenance, and escape, providing insights into potential therapeutic strategies.