Intrinsic and extrinsic regulators of cancer dormancy and awakening

Metastatic relapse is frequently driven by dormant disseminated tumor cells (DTCs) that previously evaded initial therapy, disseminated to distant tissues, entered into a non-proliferative state termed dormancy, and later reawakened to reinitiate active proliferation and the outgrowth of macroscopic metastases. Cancer dormancy manifests itself in two principal forms: cellular dormancy, characterized by the reversible, proliferative quiescence of individual cells, and tumor mass dormancy, defined by a balance between proliferation and compensating cell death. Dormant cells are notably resistant to conventional therapies and immune-mediated clearance, yet retain viability and the potential to re-enter the active cell cycle. The present review focuses on dormancy of DTCs residing in distant tissues and highlights recent advances in our understanding of both cell-intrinsic and -extrinsic regulators of cancer dormancy. Key cell-autonomous mechanisms include ERK/p38 signaling ratios, epithelial-mesenchymal plasticity, and Wnt signaling. At the same time, signals received by dormant DTCs from the adjacent tissue microenvironment-such as TGF-β family cytokines, immune surveillance, and other stromal interactions-induce and sustain dormancy. Importantly, emerging evidence suggests that microenvironmental conditions, including inflammation and aging, can trigger the awakening of dormant DTCs, leading to metastatic outgrowth. We review these evolving insights into the molecular and environmental control of cancer dormancy and awakening, underscoring their clinical relevance and therapeutic potential in preventing metastatic recurrence.