Definitions of dormancy and plasticity

Cancer dormancy

Cancer cell dormancy is an evolutionarily conserved survival strategy that enables malignant cells to endure adverse conditions by entering a hypometabolic state. Key features of dormant cancer cells include cell-cycle arrest (typically in the G0/G1 phase), chromatin condensation, and dysregulated signalling pathways. Two inter-related dormant states have been described: cellular and tumour dormancy. Cellular dormancy ( single-cell dormancy) usually occurs in disseminated tumour cells that have metastasised to distant organs; these cells can be reactivated by microenvironmental cues.17 Tumour dormancy denotes a dynamic equilibrium between cellular proliferation and death within the entire tumour mass, so that tumour volume remains stable for prolonged periods, generally owing to limited angiogenesis or immune-mediated growth suppression (Figure 1). The tumour can resume growth once environmental conditions become favourable.18 Programmed dormancy is governed by defined genetic programmes involving transcription factors such as SRY-box transcription factor 2 (SOX2) and SRY-box transcription factor 9 (SOX9), and is frequently associated with the acquisition of stem-cell-like traits by tumour cells.19

Cellular plasticity

Cancer cell plasticity is the capacity of malignant cells to alter their phenotype in response to microenvironmental changes, thereby facilitating adaptation and evolution under selective pressures such as chemotherapy or radiotherapy. This adaptive process is driven by Darwinian selection, whereby cells with advantageous traits persist and expand, ultimately contributing to tumour recurrence and metastasis.36 Specifically, plasticity encompasses (i) reversible transitions between epithelial and mesenchymal states (EMT and MET, respectively) and (ii) the acquisition or loss of stem-cell properties. EMT endows tumour cells with stemness, enabling them to remain dormant within pre-metastatic niches.15 The ability of tumour cells to modulate phenotype in response to environmental cues is therefore critical for tumour survival and progression.17 Stem-cell-like characteristics are confined to cancer stem cells (CSCs), a sub-population capable of self-renewal and multilineage differentiation.37 Plasticity allows dynamic inter-conversion between CSC and non-CSC states and represents one of the principal drivers of intratumoural heterogeneity, migration, invasion, and therapy resistance.15,17,38 (Figure 2).

Basic mechanism

Molecular crosstalk of dormancy and plasticity

Cellular plasticity is a critical determinant of tumour dissemination and distant metastasis. It enables cancer cells within the pre-metastatic niche to evade immune surveillance by undergoing epithelial-to-mesenchymal transition (EMT)7,52,53. Through this phenotypic switch, tumour cells detach more readily from the primary lesion, facilitating dissemination to secondary sites.54,55

A subsequent mesenchymal-to-epithelial transition (MET) allows disseminated cells to exit dormancy, resume proliferation, and colonise distant organs.56,57 Thus, phenotypic plasticity endows cancer cells with the adaptability required for survival, growth, and dissemination. In an evolutionary context, cellular plasticity drives both phenotypic diversification and dormancy.57 These processes recapitulate Darwinian natural selection, whereby only cells capable of phenotypic switching and dormancy survive unfavourable conditions and expand when the environment becomes permissive.58

Alternative evolutionary models—including clonal, neutral, punctuated and barrier theories—have also been proposed. These models consider stochastic mutations, non-genetic influences, and tumour–microenvironment interactions in tumour progression.59 A detailed discussion of these theories is beyond the scope of this review.

To withstand hostile cues such as immune attack or chemotherapy, tumour cells may enter dormancy. This state is orchestrated by the transcription factors TWIST1, ZEB1 and SNAI1/SNAIL, which induce EMT via p38-MAPK activation and ERK suppression, culminating in G0/G1 arrest and repression of the cell-cycle regulators NR2F1 and SOX9.39,60,61 Dormant cells simultaneously acquire stem-like traits, characterised by expression of POU5F1/OCT4, NANOG and SOX2, thereby preserving phenotypic flexibility.40,62 (Table 3) Epigenetic modifiers—including EZH2, DNA methyltransferases (DNMTs) and histone deacetylases (HDACs)—cooperate or compete to remodel chromatin, silencing proliferation-associated genes while activating survival pathways through locus-specific histone and DNA modifications.63,64,65 (Table 3)

Cell cycle regulatory networks

Cell-cycle arrest in the G0 phase constitutes a hallmark of cellular dormancy. Multiple intricate signaling cascades modulate this state. For instance, the p38 MAPK pathway suppresses cell-cycle progression by down-regulating cyclins and up-regulating CDK inhibitors, thereby enforcing dormancy31,66. The transforming-growth-factor-β (TGF-β) pathway, acting in concert with p53, induces the CDK inhibitors cyclin-dependent kinase inhibitor 2B (CDKN2B/p15), p21, and p27Kip1, similarly promoting dormancy67,68. Activation of the Notch pathway induces target genes including HES1, HEY1, MYC, cyclin D1 (CCND1), p21, and p27Kip1, thereby maintaining cells in a quiescent state and retarding tumour growth69,70.

Transcription factor networks

Signaling pathway networks

In addition to a network of regulatory and EMT-related transcription factors, signaling pathways constitute crucial regulators of cancer-cell dormancy and plasticity. Through these pathways, tumor cells can rapidly adapt to an ever-changing extracellular milieu, thereby maintaining their viability.

Network of miRNAs

MicroRNAs (miRNAs) are small, single-stranded, non-coding RNAs of approximately 20–24 nucleotides that modulate gene expression at the post-transcriptional level.98 In addition to transcriptional repression, miRNAs orchestrate diverse biological programmes, including cell growth, differentiation, proliferation and apoptosis, and help to maintain tissue homeostasis. They also participate in metabolism, immune surveillance and stress responses. Aberrant miRNA expression has been linked to numerous diseases, notably cancer, where individual miRNAs may behave as oncogenes or tumour suppressors; consequently, they are considered promising therapeutic targets.99 Several miRNAs serve as key regulators of cellular dormancy and plasticity: miR-34a, the miR-let-7 family and miR-125b control stem-cell characteristics;100,101 miR-200, miR-21 and miR-10b regulate the epithelial–mesenchymal transition (EMT);102,103,104 and miR-190, miR-223, miR-101, miR-126 and miR-26b govern cellular dormancy.105,106,107,108,109 (Tables 6 & 7).

Maintenance of cellular dormancy and reactivation of dormant cells

Factors regulating cellular dormancy, encompassing both the maintenance of dormancy and the reactivation of dormant cells (Table 8), play an important role in contemporary cancer treatment strategies. Keeping cancer cells dormant may help prevent disease progression, recurrence, and metastasis.119,120 The prevailing clinical perspective holds that preserving tumor dormancy is preferable to aggressive eradication because dormant cells proliferate slowly and frequently remain clinically silent. The central question remains: is it more beneficial to awaken dormant tumor cells to target and eliminate them, or to keep them in a dormant state? This issue has sparked significant debate within the medical community.

Some researchers have suggested that keeping tumor cells in a dormant state can be beneficial because these dormant cells are growth-inhibited and do not contribute to tumor growth or metastasis. This dormancy is believed to be maintained by the immune system and by specific signals from the microenvironment,121,122 which include a stable extracellular matrix, the suppression of angiogenesis,122,123 and surveillance by cytotoxic T cells.123,124 The focus of therapeutic efforts should be on supporting the microenvironment that allows disseminated tumor cells (DTCs) to remain dormant, rather than aggressively trying to eliminate them.71,125 Clinical observations have indicated that disruptions to this microenvironment—such as inflammation, tissue remodeling, surgery, or trauma—can reactivate dormant cells.126,127 Therefore, proponents of this approach have suggested that maintaining a stable state of dormancy may be a better strategy when cell removal is not feasible, as it may help prevent recurrence and metastasis.

Other researchers hold the opposing view that dormant tumor cells pose a long-term threat due to their unpredictable reactivation, which often leads to more aggressive disease recurrence and therapeutic resistance. These dormant cells can evade chemotherapy and radiotherapy because they are non-proliferative, allowing them to survive initial therapy.124,128,129 Once reactivated, they often acquire adaptive drug resistance, evade immune surveillance, and display an increased propensity for metastasis.129,130 For example, systemic recurrences of breast cancer and melanoma that occur 5–20 years after primary therapy are thought to result from dormant cancer cells re-entering the cell cycle. This perspective underscores the necessity for therapeutic strategies that specifically target and eradicate dormant cells.131 Potential approaches include modulation of the ERK/p38 signaling balance,132 inhibition of β1-integrin/FAK pathways,133 and enhancement of immune-mediated clearance mechanisms.124

These differing opinions highlight a significant dilemma between disease prevention and eradication. Controlled reactivation of dormant cells may have both beneficial and detrimental effects, but it also offers several therapeutic opportunities. First, reactivation can sensitize chemoresistant dormant cells to conventional treatments.21,120 Second, a planned activation–elimination strategy may help prevent late recurrence by avoiding the sudden awakening of dormant cells that leads to metastasis years later.119 Third, elucidating the pathways that regulate the re-entry of dormant cells into the cell cycle could improve our understanding of cancer progression and drug resistance.21

We contend that both therapeutic strategies—sustaining dormancy and eradicating dormant tumor cells (DTCs)—offer distinct advantages and limitations contingent upon the underlying pathobiology and available surveillance modalities. Preservation of the niche to maintain dormancy may be appropriate when the tumor microenvironment is relatively stable and robust monitoring systems are in place. Conversely, when stimuli that promote reactivation—such as inflammation, surgical trauma, or remodeling of the extracellular matrix—are present, interventions designed to detect and eliminate DTCs should be prioritized. At present, evidence is insufficient to endorse either strategy as universally superior. A pragmatic strategy is to individualize therapy according to microenvironmental attributes, biomarkers predictive of dormancy or reawakening, and patient-specific risk–benefit profiles. The principal challenge lies in determining whether dormancy is sufficiently stable to be maintained or if dormant cells are poised to reactivate. Future therapeutic paradigms will likely integrate both tactics: reinforcing the microenvironment to preserve dormancy while deploying precision agents to selectively ablate residual dormant clones. Priority research objectives include the development of biomarkers capable of quantifying dormancy stability, detecting incipient awakening, and guiding clinical trials that evaluate these combinatorial strategies.

Cellular dormancy: From evolutionary adaptation to cancer

Cellular dormancy represents an evolutionarily conserved survival strategy that enables cells to withstand adverse conditions by entering a state of reduced metabolic activity. This phenomenon is observed in organisms ranging from unicellular species that generate spores or cysts to complex multicellular species in which tissue-resident stem cells employ dormancy to facilitate tissue repair and preserve homeostasis.134,135 Underlying molecular mechanisms rely on sophisticated sensing systems mediated by G-protein-coupled receptors (GPCRs) and downstream signaling cascades, including PI3K–AKT and p38 MAPK, which ultimately activate gene programs required for spore or cyst formation and entry into dormancy.136 Cancer cells similarly deploy diverse surface receptors to detect environmental stressors: integrins sense alterations in the extracellular matrix,137 Toll-like receptors (TLRs) recognize danger-associated signals,138 receptor tyrosine kinases (RTKs) coordinate survival pathways under stress,139 and Notch receptors modulate cell-fate decisions.92 Collectively, these receptor-mediated mechanisms enable cancer cells to evade immune surveillance, acquire therapeutic resistance, and remain poised for reactivation, thereby driving disease relapse.

Cellular plasticity in evolution and adaptation to the environment

Cellular plasticity—the capacity of a cell to alter its phenotype in response to environmental cues—is critical for development, tissue repair, and disease progression.57,140 In unicellular organisms, this plasticity relies on quorum sensing and epigenetic remodeling, enabling adaptation without genetic change.141,142 In multicellular organisms, plasticity is indispensable for embryogenesis and for adaptation to environmental challenges.143 Cancer cells display pronounced plasticity, shuttling between epithelial and mesenchymal states to augment their migratory and invasive capabilities.144 This adaptability allows them to acquire stem-cell-like properties, thereby fostering tumor heterogeneity and resistance to therapy.144 Anticancer treatments impose strong selective pressures; consequently, cancer cells develop genetic or epigenetic alterations that enable them to survive through enhanced drug efflux, epigenetic reprogramming, and the activation of alternative signaling cascades, including PI3K–AKT, MAPK, and NF-κB.145

Cellular dormancy and plasticity may likewise have been pivotal for the origin and survival of early life on Earth. Only organisms capable of switching to a suitable phenotype and acquiring sufficient resistance to adverse environmental conditions could avoid extinction.134 By analogy, only tumor cells that attain stemness —cancer stem cells (CSCs)— during their lifespan can survive adverse environmental conditions and resist therapy owing to their ability to become dormant and their plasticity.7,143

Key challenges

• The lack of reliable biomarkers: Because dormant tumor cells cannot be visualized by conventional methodologies such as histopathology or standard imaging modalities, the identification and validation of robust, specific biomarkers are critical.120,166

• Drug resistance: Dormant tumor cells are arrested in the G0/G1 phase of the cell cycle, and their basal metabolism is markedly reduced, allowing them to evade therapies that target proliferating cells. Their phenotypic plasticity enables rapid switching, contributing to drug tolerance and relapse.144

• Limitations of current in vitro and in vivo models: Existing models fail to recapitulate the dormant state of tumor cells and do not accurately reproduce the tumor microenvironment (TME) or pre-metastatic niches.120,168 Consequently, therapeutic testing in these systems may yield misleading results.

• Gap in clinical translation (“the valley of death”): Although promising preclinical data have been generated for a limited number of dormancy-targeted therapies, comparable benefits have not yet been demonstrated in the clinic. Integrating such strategies into standard-of-care regimens therefore remains a substantive challenge.120

Future research directions

Cellular dormancy and cellular plasticity are recognized as pivotal drivers of cancer recurrence, yet they remain incompletely understood. Therefore, future investigations should prioritize refined methodologies that accurately identify dormant cells and either prevent their re-activation or the initiation of dormancy.

• State-of-the-art single-cell and spatial transcriptomics: Single-cell transcriptomics enables interrogation of gene-expression profiles in individual cells, facilitating the detection of cells with dormancy-associated signatures that may be missed by conventional bulk analyses. Spatial transcriptomics simultaneously maps these signatures in situ, permitting evaluation of micro-environmental cues that sustain dormancy or trigger re-awakening, and allows longitudinal tracking of phenotypic evolution that underlies drug resistance and recurrence.170

• Artificial-intelligence–driven predictive modelling: Advances in AI are ushering in a new era of understanding and managing cancer recurrence, particularly through the identification of dormant cells and characterization of cellular plasticity. With multidimensional data-integration capacity, the Clinical Histopathology Imaging Evaluation Foundation (CHIEF) model can infer tumour molecular attributes from histological images, aiding in the recognition of dormant cells that pose a risk of relapse.171 AI-based platforms can also synthesise genomic, transcriptomic, proteomic and epigenomic data, enabling comprehensive appraisal of tumour biology, refined recurrence prediction and subsequent personalisation of therapeutic regimens and follow-up.172

• Targeting epigenetic and metabolic vulnerabilities: Epigenetic analyses can reveal chromatin states that permit tumour cells to persist in dormancy, and pharmacological modulation of these states can suppress EMT by regulating pertinent genes.173 Metabolic profiling can distinguish dormant cells by their low-flux signatures—such as reliance on oxidative phosphorylation and fatty-acid oxidation—thereby differentiating them from proliferative counterparts. Because metabolic and epigenetic programmes interact to dictate cancer-cell state, co-targeting both processes may enhance therapeutic efficacy and diminish recurrence risk.174

• Modulating the tumour micro-environment (TME): Dormancy is maintained by TME factors including hypoxia, cytokine milieu and extracellular-matrix stiffness, which also foster immune evasion and drug resistance.175 Strategies that re-engineer the TME—e.g., adjusting pH, oxygenation or extracellular-matrix composition—to improve drug penetration, invigorate antitumour immunity and curtail dormant-cell survival are therefore under active investigation.176