The awakening of dormant disseminated cancer cells appears to be responsible for the clinical relapses of patients whose primary tumors have been successfully cured months and even years earlier. In the present study, we demonstrate that dormant breast cancer cells lodged in the lungs reside in a highly mesenchymal, nonproliferative phenotypic state. The awakening of these cells is not triggered by a cancer cell-autonomous process. Instead, lung inflammation induced by the chemotherapeutic agent bleomycin effectively awakens dormant cancer cells, providing useful models for studying metastatic awakening. Mechanistically, the awakened cells shift from a highly mesenchymal to a quasi-mesenchymal phenotypic state in which they acquire tumorigenicity and proliferative ability. Once awakened, these cells can stably reside in this quasi-mesenchymal state and maintain their tumor-initiating ability, doing so without ongoing heterotypic signaling from the lung microenvironment. Epidermal growth factor receptor ligands released by the cells of the injured tissue microenvironment, including notably M2 type macrophages, promote dormant cancer cells to move toward this quasi-mesenchymal state, a transition that is critical for the awakening process. An understanding of the mechanisms of metastatic awakening may lead in the future to treatment strategies designed to prevent such awakening and resulting metastatic relapse.

Cancer cells that survive therapeutic drug pressure are a significant cause of disease relapse and progression, impeding curative cancer treatment. Drug-triggered Darwinian selection and the emergence of subclones harbouring specific mutations that confer resistance have been well documented and extensively studied. However, these genetic alterations, while important, do not fully explain clinical observations where some patients, after a drug holiday, regain sensitivity to the same treatment despite previous disease progression. This phenomenon highlights the possibility that drug resistance may not solely rely on genetic mutations but could also involve reversible, non-genetic mechanisms. Recent studies have highlighted the existence of drug-tolerant persister cells (DTPs), a subpopulation of cancer cells that can survive short-term therapeutic pressure without acquiring resistance-associated genetic alterations. These cells exhibit a temporary yet reversible tolerance to the initial treatment while also acquiring cross-tolerance to other anti-cancer therapies. The presence of DTPs underscores a dynamic and complex plasticity in tumours, wherein cancer cells can utilise epigenetic rewiring, metabolic reprogramming, and specific signalling pathways to transit between drug-tolerant and drug-sensitive states to adapt to environmental pressures. Furthermore, this adaptive resilience enables DTPs to act as a reservoir for the development of genetically stable resistance, resulting in cancer therapy failure and eventual relapse. In this mini-review, we examine recent evidence on DTPs to provide an overview of their characteristics, development, and survival mechanisms.

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.