Dormancy and reactivation of disseminated tumor cells: From molecular mechanisms to therapeutic implications

Metastasis and cancer recurrence post-treatment continue to pose significant challenges to patients' long-term survival. This phenomenon can be ascribed to metastatic tumor dormancy. Dormant tumor cells, as a critical stage in malignant tumor progression, are characterized by their induction of cell cycle arrest and survival in a quiescent state. These cells adapt to the heterogeneous microenvironment through genetic and epigenetic reprogramming, evading therapeutic pressure and immune surveillance. Under favorable conditions, dormant disseminated tumor cells (DTCs) may be reactivated, leading to proliferation and colonizing distant organs, forming clinically detectable metastatic lesions. The dynamic transition between dormancy and reactivation renders it one of the most challenging aspects of tumor eradication. This review examines the life cycle regulation of dormant tumor cells within the metastatic microenvironment, systematically delineating the intracellular and extracellular molecular mechanisms that govern their induction, maintenance, and reactivation. We highlight the synergistic roles of multilayered networks, including signaling pathway crosstalk, epigenetic regulation, metabolic and autophagic adaptation, extracellular matrix remodeling, and immune regulation. This review summarizes and evaluates the primary therapeutic strategies targeting dormant DTCs, including their associated risks and potential for clinical translation, aiming to provide a comprehensive theoretical framework and intervention strategies to delay or prevent tumor recurrence and metastasis.