Remodeling the tumor dormancy ecosystem to prevent recurrence and metastasis

Dormant tumor cells, major contributors to tumor recurrence and metastasis, are characterized by cell cycle arrest and reactivation potential. Tumor dormancy arises from the dynamic interplay between intrinsic tumor properties and extrinsic factors within the tumor ecosystem. This ecosystem operates at two distinct levels: the tumor microenvironment (TME) and the systemic macroenvironment (SME). Within the dormant TME, tumor cells engage in complex interactions with surrounding stromal cells, extracellular matrix components, and the vasculature, which are mediated through growth factors, cytokines, and metabolic byproducts. At the systemic level, the SME modulates tumor dormancy via inflammatory responses, metabolic homeostasis, hormonal regulation, and neural signaling. The TME and SME collectively maintain tumor dormancy through their bidirectional crosstalk. Disruption of this delicate ecological equilibrium can trigger tumor reactivation and metastatic progression. Consequently, effective therapeutic strategies should simultaneously target both TME remodeling and SME modulation. In this review, we provide a comprehensive analysis of the coordinated roles of the TME and SME in regulating tumor cell dormancy and reactivation while summarizing potential therapeutic approaches and clinical trials aimed at either eliminating dormant tumor cells or sustaining dormancy. Consequently, we propose a novel two-dimensional combined treatment strategy that concurrently addresses both the TME and SME to prevent tumor recurrence and metastasis.