Tumor dormancy and ageing: Understanding cancer recurrence

Abstract

Cancer recurrence remains a leading cause of mortality in patients with solid tumors. Early disseminated tumor cells (DTCs), which seed distant organs during the initial stage of tumor progression, are widely recognized as an important source of late metastatic relapse. Tumor cell dormancy, a reversible but prolonged non-proliferative state, enables DTCs to survive in metastatic tissues for years or even decades before re-entering the cell cycle and giving rise to overt metastases. Accumulating evidence indicates that dormancy is regulated by both cell-intrinsic mechanisms, such as epigenetic reprogramming and metabolic adaptation, and extrinsic cues from the tissue microenvironment. Among these extrinsic regulators, ageing has emerged as a critical determinant of DTC fate by profoundly remodeling tissue microenvironments through cellular senescence, chronic inflammation, extracellular matrix (ECM) remodeling, vascular dysfunction, stromal metabolic rewiring, and immune dysregulation. These ageing-associated alterations progressively erode dormancy-supportive niches, thereby leading to metastatic reactivation. In this Review, we summarize the molecular mechanisms governing tumor dormancy and discuss how ageing-associated microenvironmental remodeling contributes to the reactivation of dormant DTCs. We highlight the roles of the senescence-associated secretory phenotype (SASP), ECM remodeling, vascular deterioration, and organ-specific stromal ageing in regulating the maintenance and exit of tumor dormancy. We also discuss emerging translational opportunities, including dormancy-reinforcing therapies, senolytic strategies, liquid biopsy-based surveillance, and advanced experimental platforms such as single-cell and spatial technologies. Collectively, this Review provides a conceptual framework for understanding how ageing progressively modulates tumor dormancy and highlights potential strategies to prevent late metastatic recurrence.