Decoding the metabolic cipher of dormant cancer cells: molecular mechanisms and therapeutic potentials

Dormant cancer cells (DCCs) are non-proliferative cancer cells that enter cell cycle arrest in the G0-G1 phase and are recognized as a major cause of therapeutic resistance and cancer recurrence. In response to various intracellular and extracellular signals, DCCs undergo cellular reprogramming that confers drug resistance and enables them to evade immune surveillance. Once reactivated, these cells can resume proliferation, ultimately leading to tumor relapse. Metabolic reprogramming allows DCCs to adapt to the nutrient-deprived tumor microenvironment (TME), reduce energy consumption, and maintain redox homeostasis. Targeting these metabolic vulnerabilities provides promising opportunities to control recurrence and improve therapeutic outcomes. However, the metabolic reprogramming of DCCs is highly heterogeneous, which poses a major challenge for their complete eradication. In this review, we summarize the metabolic features of DCCs, describe the molecular mechanisms underlying metabolic reprogramming across distinct DCC subtypes, elucidate the interactive networks among distinct metabolic pathways, and discuss therapeutic strategies targeting metabolism of DCCs, with the goal of providing new insights into improving treatment efficacy and preventing recurrence.