INTRODUCTION

Despite remarkable advances in the field of oncology, cancer continues to be a leading cause of mortality worldwide [1]. Growing evidence points to the emergence of dormant cells as a contributor to the disease's aptitude to evade therapeutic interventions [2,3▪,4,5,6▪]. In this context, cellular dormancy refers to cells entering a prolonged state of reduced proliferation, where growth is considerably slowed down or halted [7▪,8]. This concept overlaps largely with other programs of proliferative arrest, specifically quiescence (i.e. the reversible state of G0/G1 cell cycle arrest) and replicative senescence (i.e. the cessation of cell division due to cellular aging and replication limits) [9▪]. Beyond proliferation, the phenotypic switch of cellular dormancy is characterized by a substantial decrease in biosynthetic activity, such as RNA transcription and protein translation [10,11]. Concomitantly, dormant cells appear to undergo a deep metabolic rewiring, as energy and metabolite requirements are often linked to growth and proliferation [12,13].

Cellular dormancy is an evolutionarily conserved adaptation, typically employed by stem and progenitor cells in-between bursts of proliferative phases [7▪]. As described in 1954, malignant cells can spontaneously enter dormancy, explaining the latency between cancer dissemination and clinical relapse, often spanning years [14]. Ongoing investigations have since expanded the concept beyond metastases and significantly enriched our comprehension of the underlying molecular mechanisms (Fig. 1) [3▪,15▪]. Dormant cells usually constitute a minor fraction of unchallenged parental tumors (<5%), but many cancer therapies promote their emergence [16–18]. Indeed, reduced proliferative cycling and metabolic activity inherently renders cells more tolerant to a variety of chemotherapeutic agents [6▪]. Thereby, while the bulk of a tumor may respond to a given therapy and undergo elimination, a small subset of cells, referred to as drug-tolerant persisters (DTPs), can evade eradication by switching to a dormant phenotype [2,5,11,19]. Likewise, during cancer progression, disseminated tumor cells (DTCs) can also remain dormant for several years after spreading to a secondary site, explaining the long delays observed before clinical relapse [3▪,8]. Overall, the continued presence of DTPs and DTCs creates a latent reservoir for the tumor, which over time may lead to the accumulation of new oncogenic mutations and the acquisition of stable resistance mechanisms [11,20▪▪]. In time, dormant cells may be reactivated, leading to a secondary tumor or metastatic relapse. Consequently, dormant cells contribute to the persistence of cancer, both at primary and secondary sites, and undermine the effectiveness of therapeutic approaches.

FIGURE 1:

Cellular dormancy during tumorigenesis. (a) Dormancy arises throughout cancer progression. Top: Rare dormant cells can spontaneously appear in unchallenged tumors. Cancer cells can also adopt a reversible dormant phenotype in response to chemotherapy, referred to as ‘posttherapy dormancy’. This phenotypic switch allows the persistence of cancer cells in the form of drug-tolerant persisters (DTPs). DTPs are still sensitive to treatment and can remain below the level of clinical detection for an extended period of time. Reawakening of dormant cells and tumor regrowth occurs following treatment cessation and/or emergence of drug-resistance mechanisms. Bottom: Disseminated tumor cells (DTCs) that have spread to a secondary site also enter dormancy and remain in this state for several months or years. This phenomenon, coined as ‘metastatic dormancy’, explains the long delays frequently observed before metastatic relapse occurs in patients. (b) Features of dormant cancer cells (common to posttherapy and metastatic dormancy) differ largely from those of drug-resistant tumors and metastases.

Understanding the mechanisms of cellular dormancy is of utmost importance in the fight against cancer. In this review, we delve into the intricacies of cancer dormancy, focusing on the emergence and characteristics of DTPs and DTCs. By exploring their significance in promoting resistance and disease progression, we aim to shed light on potential avenues for combating the persistence of malignant cells and enhancing therapeutic interventions. 

Box 1:

no caption available

EXPLORING THE ROOTS OF CANCER DORMANCY

The rising recognition of cancer dormancy is underscored by the ever-growing list of treatments known to induce DTPs, whether used alone or in combination, and across multiple cancer types. These therapies now encompass alkylating agents, antimetabolites, topoisomerase and mitotic inhibitors, and more [5,6▪,11,20▪▪,21▪▪]. Furthermore, the capacity of epidermal growth factor receptor (EGFR), mechanistic target of rapamycin (mTOR) and enhancer of zeste homolog 2 (EZH2) inhibitors to promote the emergence of DTPs in response to many of the aforementioned chemotherapies highlights the importance of careful consideration in choosing treatment combinations [6▪,20▪▪,22].

An intriguing question arises: where do DTPs stem from? Barcoding experiments on models of posttherapy dormancy revealed that nondividing persisters exhibit little to no clonal selection compared to parental tumors, with all cells having similar chances of entering dormancy [5,11,19,20▪▪,23,24▪]. Thus, Rehman et al.[11] suggested that the observed barcode complexity did not support the selection of cells based on fitness differences. Instead, stochastic delays in transitioning from the nondividing state of persisters back into active proliferation after treatment cessation could account for minor alterations in clonal diversity. Beyond this equipotent model, several groups proposed that rare dormant cells that spontaneously appear in unchallenged tumors are primed to preferentially generate DTPs during treatment [20▪▪,23,24▪]. The evidence to-date is mostly based on transcriptomic and epigenomic similarities, as classical lineage tracing methods are complicated by the nondividing nature of DTPs. Nevertheless, Oren et al.[25] used a sophisticated barcoding approach to identify a rare subpopulation of proliferative cells among cancer persisters, illustrating the heterogeneity found among dormant cells. Importantly, cancer persisters also act as a reservoir for the development of stably resistant clones, which are characterized by active proliferation even under treatment and numerous acquired mutations. Intriguingly, despite not being driven by genetic mechanisms themselves, DTPs can nonetheless exhibit a rise in their mutational rate, thus promoting the development of drug-resistant clones [26▪▪]. And unlike DTPs, the emerging resistant tumors experience a marked reduction in clonal diversity, in line with a model of mutations followed by genetic selection [11,20▪▪].

Addressing the origin of DTCs proves even more challenging, as metastatic spreading is a complex multistep process. Early stages of dissemination are known to be subject to clonal selection and phenotypic adaptation [3▪,27]. In contrast, emerging evidence suggests that the initiation of dormancy, which follows the dissemination of cells, may not rely on genetic mechanisms and clonal selection. Circulating tumor cells and DTCs have indeed been found to exhibit comparable levels of clonal diversity [27], hinting at a potential application of the equipotent model of DTPs to DTCs. However, further evidence is required to substantiate this hypothesis. Interestingly, this notion aligns with prior work indicating that quiescence might be inevitable in disseminated cells, with bottleneck events lying rather in the subsequent reactivation of proliferation and the transition from micro- to macro-metastases [15▪].

The pervasiveness of dormancy may come from its connections to many established hallmarks of cancer – such as resistance to cell death, genomic mutations, deregulation of metabolism and metastases [28,29▪]. Similarly, the transient nature of dormancy, wherein cells eventually resume active proliferation, reflects cancer's inherent ability to evade growth suppression mechanisms and sustain proliferative signaling – further reinforcing the association between dormancy and cancer hallmarks [30]. Furthermore, cellular dormancy constitutes a widespread survival strategy against adverse environments. One of the most striking examples of such an adjustment in nature is diapause, in which species reversibly suspend their embryonic development, sometimes for several months, if environmental conditions are unfavorable for embryo growth and maturation [31–33]. Phenotypic and transcriptional parallels have been drawn between diapause and various models of cancer dormancy, implying that tumors may be ‘hijacking’ an evolutionarily conserved mechanism [11,19,32,34,35].

MOLECULAR MECHANISMS SUSTAINING DORMANCY: FROM TRANSCRIPTIONAL PLASTICITY TO THE TUMOR MICROENVIRONMENT

As research into cancer dormancy progresses, a clearer picture of its extensive molecular reshaping is emerging (Fig. 2), albeit with some heterogeneity observed between models [20▪▪,24▪]. Most strikingly, proliferation is sharply decreased in DTPs and DTCs, observed either through slow cell cycling or transient G0/G1 arrest [11,20▪▪,24▪]. Consequently, many transcriptional pathways typically associated with proliferation and growth are repressed, including Myc, mTOR and cell-cycle related signaling, leading to a state of global hypotranscription [11,19,34]. A reduction in the dependency on glycolysis and a shift towards oxidative phosphorylation have been observed in many preclinical models of dormancy [11,36▪]. Conversely, induction of autophagy plays a key role in mediating the survival of dormant cells [13,37,38]. Alongside mTOR suppression, AMPK, MAPK p38 and ERK1/2 have all been independently implicated in the upregulation of autophagy, further promoting the viability of persister cells [11,37,38]. Another notable attribute of dormant cells is the contribution of transcriptional programs promoting epithelial-to-mesenchymal transition (EMT), such as Sonic Hedgehog (SHH), Wnt and transforming growth factor beta (TGF-β) signaling [20▪▪,21▪▪,24▪,34]. However, others have observed suppressed Wnt activity, with the Hippo pathway supporting EMT instead [39▪▪,40].

FIGURE 2:

Molecular mechanisms underlying cellular dormancy in cancer. Dormant cancer cells are regulated by a network of intrinsic and extrinsic factors that suppress proliferation and promote drug-tolerance. Dysregulation of key transcriptional programs, epigenetic processes, and bioenergetic pathways, intertwined with the acquisition of senescent traits and a pro-dormancy tumor microenvironment, collectively form a multifaceted regulatory web.

An intriguing feature that has been noted across various cancer dormancy models is the emergence of senescent traits, encompassing the senescence-associated secretory phenotype (SASP) and expression of the β-galactosidase marker [6▪,22,34,41▪]. Within the context of cancer dormancy, senescence can restrain both proliferation and drug-induced apoptosis [42▪]. Intriguingly, the SASP exhibits higher metabolic demands, which could be dependent on mTOR-driven activation of glycolysis, in contrast to the typical shift towards oxidative phosphorylation [36▪,43,44]. Alternatively, activation of the tumor suppressor p53 has been implicated in cell cycle impairment and senescence, and exit from dormancy may require reduced p53 activity [45▪]. Moreover, Liu et al. found that the gain-of-function mutations p53R273H and p53R249S, which are frequently identified in human cancers and associated with increased cell survival, can facilitate the drug-tolerant state [6▪,45▪]. Similarly, entry into replicative senescence may be dependent on the checkpoint kinase ATR, which acts upstream of p53, as well as the sublethal release of cytochrome c[21▪▪,34]. The balance between proliferation, senescence and apoptosis, orchestrated by p53 and/or other related factors, is thereby critical to the establishment of the dormant persister phenotype.

Considering the profound alterations displayed by dormant cancer cells, it is remarkable that this plasticity doesn’t stem from new genetic mutations or clonal selection, as demonstrated through barcoding experiments [5,11,20▪▪]. Instead, the switch appears to be largely supported by reversible changes at the chromatin level. Along with mTOR suppression, decreased activity of the Myc oncogene drives much of the transcriptional and metabolic repression seen in dormant cells, instigating a diapause-like state with reduced apoptotic priming [11,19,46,47▪]. In response to pro-apoptotic therapy, activating transcription factor 4 (ATF4) initiates, independently of caspases, a gene expression program that supports DTP survival by promoting autophagy and preventing oxidative stress [21▪▪]. The nuclear hormone receptor NR2F1 is another transcriptional regulator that promotes dormancy of various types of cancer cells and was found upregulated in in vivo models of DTCs [48▪,49,50]. Furthermore, extensive epigenetic changes are now being unveiled in dormant cells, echoing pioneer studies that identified chromatin-modifying agents as regulators of the DTP state [2,51,52]. Using single-cell technologies, Marsolier et al.[20▪▪] revealed that the persister transcriptional program is primed by H3K4me3 and H3K27me3 (trimethylation of histone H3 at lysine 4 and 27, respectively) in unchallenged mammary tumor cells. Depletion of H3K27me3, through inhibition of the methyltransferase EZH2, promotes the transition to a drug-tolerant state by unlocking the expression of key transcription factors. Interestingly, a global increase in DNA methylation was observed in persister cells from acute myeloid leukemia, and various regulators of dormancy were shown to be regulated through promoter methylation [34,49,53▪]. Future work may further define the extent of chromatin rewiring underlying cancer dormancy.

It is also important to recognize that the induction of a dormant program is not an isolated, cell-autonomous process. In particular, the tumor microenvironment (TME), encompassing both stromal cells and extracellular matrix (ECM), plays a critical role in the establishment of metastatic dormancy [4,15▪]. Both intrinsic and extrinsic factors of the TME can sustain dormancy, such as TGF-β, WNT5a, several laminins and collagens [54▪,55▪,56▪,57,58▪]. Additionally, immune cells are vital components of the TME, and several studies highlight the involvement of specific subpopulations of T cells and natural killer (NK) in initiating metastatic dormancy, notably through the pivotal roles of tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ) [41▪,59,60]. Of note, cytokine-induced dormancy has been linked to the emergence of the senescent phenotype in dormant cells [34,41▪]. Other populations of cells, such as cancer-associated fibroblasts (CAFs) in the lung and mesenchymal stem cells in the bone marrow, were found to serve as sources of dormancy-modulating cytokines, including TGF-β and interleukin-6 [23,61]. Furthermore, the TME can also influence cancer dormancy by affecting tumor oxidative stress, especially in persister cells [19,21▪▪]. Activation of the MAPK p38, a common characteristic of DTPs, is indeed redox-dependent and it operates upstream of two vital mediators of cancer dormancy, namely NR2F1 and p53 [62–64]. Reactive oxygen species (ROS) can also influence, directly or indirectly, a number of signaling pathways involved in cancer dormancy, including TGF-β, SHH, Wnt, mTOR and autophagy [63,65,66]. In conclusion, the TME serves various functions that support local dormant niches and plays a crucial role in balancing cellular dormancy and reactivation of proliferation.

TACKLING THE DILEMMA OF CANCER DORMANCY AND RELAPSE PREVENTION

Three main strategies have been investigated to prevent dormant cells from becoming a potent source of therapy resistance and clinical relapse [67,68]. Firstly, research groups have sought to directly eliminate putative dormant cells by identifying essential pathways shared across multiple preclinical models. For example, autophagy inhibitors efficiently trigger apoptosis and eliminate colorectal cancer persister cells, and these outcomes were replicated in various other cancer types [6▪,11,38]. A clinical trial evaluating such approach in the context of mammary DTC is currently in phase II (NCT04841148). While promising, it remains to be shown how effective such approach would be when applied to a large clinical setting. Secondly, studies have sought to sustain dormancy long-term [67,68]. For instance, interleukin-15 administration in mouse models recruits NK cells, maintains dormancy through IFN-γ signaling, and prevents hepatic metastases, thus extending survival [59]. Likewise, a recent Phase II clinical trial (NCT03572387) explored using retinoic acid combined with 5-azacytidine to sustain dormancy in head and neck squamous cell carcinoma. Pausing disease progression may be particularly beneficial for patients at high risk of recurrence. However, maintaining dormancy alone, possibly through lifelong treatment, would likely not eliminate DTPs and DTCs, which could eventually develop resistance mechanisms. In contrast to the last approach, the third strategy aims instead to reawaken dormant cells in order to re-sensitize them to cytotoxic treatments [67,68]. This approach mirrors the ‘shock-and-kill’ strategy employed against HIV: latency-reversing agents awaken dormant viral particles concealed within immune cells, enabling their targeted elimination by the immune system or anti-HIV drugs [69]. In the context of cancer dormancy, this may notably be achieved through modulation of the signals arising from the tumor niche. For instance, inhibition of integrin-mediated interactions with the perivascular niche sensitizes disseminated tumor cells to chemotherapy [70]. A major caveat of this approach, however, is the risk to promote disease progression as dormant cells reawaken, which may restrict its clinical use in the immediate future.

In recent years, immunotherapy has gained attraction as a promising cancer treatment, although success rates vary widely between cancer types [71]. Cancer dormancy and immunotherapy share a complex, bidirectional relationship. On one hand, dormancy-induced resistance can hinder the efficacy of such therapy. Indeed, dormant cancer cells can oppose T cells by forming an immunosuppressive niche [72▪▪]. On the other hand, cytokine and antibody-based approaches have the potential to both sustain dormancy or reawaken persisters, either through modulation of the TME or by directly targeting dormant cells [41▪,60,70]. One such example is the identification of the stimulator of interferon genes (STING) pathway as an inhibitor of dormancy reactivation, with agonist administration in mice eliminating dormant metastasis in a T and NK cell-dependent manner [73▪▪]. Thus, harnessing the full potential of immunotherapeutic approaches may prove critical in the efficient management of cancer dormancy.

MEETING THE CHALLENGES AHEAD

Our understanding of the intricate molecular mechanisms driving cancer dormancy is continually growing, revealing potential pathways that could be targeted for therapeutic interventions. Nonetheless, many challenges remain. To date, most studies have relied on bulk sequencing methods, with only a few taking advantage of single-cell transcriptomics [23,24▪,57,60]. As noted by Oren et al.[25], factors contributing to persister-driven relapse are difficult to discern using bulk profiling since most persisters remain arrested during drug treatment. Thus, the heterogeneity of subpopulations within dormant malignant cells should be further explored at the single-cell level across a variety of regulatory mechanisms, such as recruitment of transcription factors and epigenetics [20▪▪]. Likewise, while in vitro models are becoming more complex with the rise of 3D cultures and organoids, only in vivo models can fully replicate a dormant niche and its complex TME interplay. Even then, orthopedic transplants and patient-derived xenografts (PDXs), which are widely used to study cancer dormancy in vivo, rely on the use of immunocompromised mice [11,20▪▪]. Given the growing interest in both the role of the TME and immunotherapies, transgenic mouse models could provide a valuable platform [67]. While acknowledging the concern about representing a diverse clonal population of cells, genetically engineered mouse models could play a pivotal role in exploring the mechanisms underlying DTPs and DTCs within immunocompetent environments. As clinical trials exploring posttherapy and metastatic dormancy are just in their infancy, bridging the gap between preclinical models and patient care represents a critical undertaking, now more than ever.

CONCLUSION

Investigation into cancer dormancy has progressed by leaps and bounds over the past decade, due in no small part to improvements in experimental and patient-derived models, and molecular technologies. The insights gained through these advancements shed a light on a path towards more effective therapeutic strategies. By unraveling the intricate mechanisms governing dormancy, we move closer to preventing clinical relapse and improving patient outcomes. The journey ahead is still long, however, and beckons further exploration and innovations in the pursuit to conquer cancer dormancy.

Acknowledgements

We would like to thank Dr Sumaiyah Rehman for feedback on the manuscript.

Financial support and sponsorship

This work was supported by the Belgian ‘Fonds de la Recherche Scientifique’ (F.N.R.S.) through a fellowship to E.C., by the Fund Suzanne Duchesne, Serge Rousseau and Docteur Jean Gérard and by the Funds André Vander Stricht, Emile Carpentier, Van Damme, Yvonne & Jacques François – De Meurs, José Plé - Albert Declercq, Daisy Jacobs, Blondine and, Van der Poorten - Vemreiren, managed by the King Baudouin Foundation.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

REFERENCES 1. Pilleron S, Alqurini N, Ferlay J, et al. International trends in cancer incidence in middle-aged and older adults in 44 countries. J Geriatr Oncol 2022; 13:346–355. 2. Sharma SV, Lee DY, Li B, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 2010; 141:69–80. 3▪. Gerstberger S, Jiang Q, Ganesh K. Metastasis. Cell 2023; 186:1564–1579. 4. Giancotti FG. Mechanisms governing metastatic dormancy and reactivation. Cell 2013; 155:750. 5. Echeverria GV, Ge Z, Seth S, et al. Resistance to neoadjuvant chemotherapy in triple-negative breast cancer mediated by a reversible drug-tolerant state. Sci Transl Med 2019; 11:936. 6▪. Liu Y, Azizian NG, Sullivan DK, Li Y. mTOR inhibition attenuates chemosensitivity through the induction of chemotherapy resistant persisters. Nat Commun 2022; 13:7047. 7▪. Min H-Y, Lee H-Y. Cellular dormancy in cancer – mechanisms and potential targeting strategies. Cancer Res Treat 2023; 55:720–736. 8. Gelman IH. The genomic regulation of metastatic dormancy. Cancer Metastasis Rev 2023; 42:255–276. 9▪. Truskowski K, Amend SR, Pienta KJ. Dormant cancer cells: programmed quiescence, senescence, or both? Cancer Metastasis Rev 2023; 42:37–47. 10. Bulut-Karslioglu A, Biechele S, Jin H, et al. Inhibition of mTOR induces a paused pluripotent state. Nature 2016; 540:119–123. 11. Rehman SK, Haynes J, Collignon E, et al. Colorectal cancer cells enter a diapause-like DTP state to survive chemotherapy. Cell 2021; 184:226–242. e21. 12. Tau S, Miller TW. The role of cancer cell bioenergetics in dormancy and drug resistance. Cancer Metastasis Rev 2023; 42:87–98. 13. Li Y, Chen H, Lu D, et al. Mitophagy is a novel protective mechanism for drug-tolerant persister (DTP) cancer cells. Autophagy 2023; 19:2618–2619. 14. Hadfield G. The dormant cancer cell. Br Med J 1954; 2:607–610. 15▪. Elkholi IE, Lalonde A, Park M, Côté JF. Breast cancer metastatic dormancy and relapse: an enigma of microenvironment(s). Cancer Res 2022; 82:4497–4510. 16. Mirza S, Sharma G, Pandya P, Ralhan R. Demethylating agent 5-aza-2-deoxycytidine enhances susceptibility of breast cancer cells to anticancer agents. Mol Cell Biochem 2010; 342:101–109. 17. Guler GD, Tindell CA, Pitti R, et al. Repression of stress-induced LINE-1 expression protects cancer cell subpopulations from lethal drug exposure. Cancer Cell 2017; 32:221–237. e13. 18. Liau BB, Sievers C, Donohue LK, et al. Adaptive chromatin remodeling drives glioblastoma stem cell plasticity and drug tolerance. Cell Stem Cell 2017; 20:233–246. e7. 19. Dhimolea E, de Matos Simoes R, Kansara D, et al. An embryonic diapause-like adaptation with suppressed myc activity enables tumor treatment persistence. Cancer Cell 2021; 39:240–256. e11. 20▪▪. Marsolier J, Prompsy P, Durand A, et al. H3K27me3 conditions chemotolerance in triple-negative breast cancer. Nat Genet 2022; 54:459–468. 21▪▪. Kalkavan H, Chen MJ, Crawford JC, et al. Sublethal cytochrome c release generates drug-tolerant persister cells. Cell 2022; 185:3356–3374. e22. 22. Kurppa KJ, Liu Y, To C, et al. Treatment-induced tumor dormancy through YAP-mediated transcriptional reprogramming of the apoptotic pathway. Cancer Cell 2020; 37:104–122. e12. 23. Moghal N, Li Q, Stewart EL, et al. Single-cell analysis reveals transcriptomic features of drug-tolerant persisters and stromal adaptation in a patient-derived EGFR-mutated lung adenocarcinoma xenograft model. J Thorac Oncol 2023; 18:499–515. 24▪. Chang CA, Jen J, Jiang S, et al. Ontogeny and vulnerabilities of drug-tolerant persisters in HER2+ breast cancer. Cancer Discov 2022; 12:1022–1045. 25. Oren Y, Tsabar M, Cuoco MS, et al. Cycling cancer persister cells arise from lineages with distinct programs. Nature 2021; 596:576–582. 26▪▪. Russo M, Pompei S, Sogari A, et al. A modified fluctuation-test framework characterizes the population dynamics and mutation rate of colorectal cancer persister cells. Nat Genet 2022; 54:976–984. 27. Maeshiro M, Shinriki S, Liu R, et al. Colonization of distant organs by tumor cells generating circulating homotypic clusters adaptive to fluid shear stress. Sci Rep 2021; 11:6150. 28. Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov 2022; 12:31–46. 29▪. Tu SM, Estecio MR, Lin SH, Zacharias NM. Stem cell theory of cancer: rude awakening or bad dream from cancer dormancy? Cancers (Basel) 2022; 14:655. 30. Tomasin R, Bruni-Cardoso A. The role of cellular quiescence in cancer – beyond a quiet passenger. J Cell Sci 2022; 135:jcs259676. 31. Fenelon JC, Renfree MB. The history of the discovery of embryonic diapause in mammals. Biol Reprod 2018; 99:242–251. 32. Hussein AM, Balachandar N, Mathieu J, Ruohola-Baker H. Molecular regulators of embryonic diapause and cancer diapause-like state. Cells 2022; 11:2929. 33. Garcia-Ojalvo J, Bulut-Karslioglu A. On time: developmental timing within and across species. Development 2023; 150:dev201045. 34. Duy C, Li M, Teater M, et al. Chemotherapy induces senescence-like resilient cells capable of initiating AML recurrence. Cancer Discov 2021; 11:1542. 35. Manoir S Du, Delpech H, Orsetti B, et al. In high grade ovarian carcinoma, platinum-sensitive tumor recurrence and acquired-resistance derive from quiescent residual cancer cells that overexpress CRYAB, CEACAM6 and SOX2. J Path 2022; 257:367–378. 36▪. Tau S, Miller TW. The role of cancer cell bioenergetics in dormancy and drug resistance. Cancer Metastasis Rev 2023; 42:87–98. 37. You B, Xia T, Gu M, et al. AMPK-mTOR-mediated activation of autophagy promotes formation of dormant polyploid giant cancer cells. Cancer Res 2022; 82:846–858. 38. Tian X, He Y, Qi L, et al. Autophagy inhibition contributes to apoptosis of PLK4 downregulation-induced dormant cells in colorectal cancer. Int J Biol Sci 2023; 19:2817–2834. 39▪▪. Álvarez-Varela A, Novellasdemunt L, Barriga FM, et al. Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy. Nat Cancer 2022; 3:1052–1070. 40. Lavado A, Park JY, Paré J, et al. The hippo pathway prevents YAP/TAZ-driven hypertranscription and controls neural progenitor number. Dev Cell 2018; 47:576–591.e8. 41▪. Homann L, Rentschler M, Brenner E, et al. IFN-γ and TNF induce senescence and a distinct senescence-associated secretory phenotype in melanoma. Cells 2022; 11:1514. 42▪. Saleh T, Gewirtz DA. Considering therapy-induced senescence as a mechanism of tumour dormancy contributing to disease recurrence. Br J Cancer 2022; 126:1363–1365. 43. Dörr JR, Yu Y, Milanovic M, et al. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 2013; 501:421–425. 44. Kunimasa K, Nagano T, Shimono Y, et al. Glucose metabolism-targeted therapy and withaferin A are effective for epidermal growth factor receptor tyrosine kinase inhibitor-induced drug-tolerant persisters. Cancer Sci 2017; 108:1368–1377. 45▪. Bui T, Gu Y, Ancot F, et al. Emergence of β1 integrin-deficient breast tumours from dormancy involves both inactivation of p53 and generation of a permissive tumour microenvironment. Oncogene 2022; 41:527–537. 46. Scognamiglio R, Cabezas-Wallscheid N, Thier MC, et al. Myc depletion induces a pluripotent dormant state mimicking diapause. Cell 2016; 164:668–680. 47▪. Collignon E, Cho B, Furlan G, et al. m6A RNA methylation orchestrates transcriptional dormancy during paused pluripotency. Nat Cell Biol 2023; 25:1279–1289. 48▪. Borriello L, Coste A, Traub B, et al. Primary tumor associated macrophages activate programs of invasion and dormancy in disseminating tumor cells. Nat Commun 2022; 13:626. 49. Sosa MS, Parikh F, Maia AG, et al. NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes. Nat Commun 2015; 6:6170. 50. Wu R, Roy AM, Tokumaru Y, et al. NR2F1, a tumor dormancy marker, is expressed predominantly in cancer-associated fibroblasts and is associated with suppressed breast cancer cell proliferation. Cancers (Basel) 2022; 14:2962. 51. Evertts AG, Manning AL, Wang X, et al. H4K20 methylation regulates quiescence and chromatin compaction. Mol Biol Cell 2013; 24:3025–3037. 52. Clements ME, Holtslander L, Edwards C, et al. HDAC inhibitors induce LIFR expression and promote a dormancy phenotype in breast cancer. Oncogene 2021; 40:5314–5326. 53▪. Singh DK, Carcamo S, Farias EF, et al. 5-Azacytidine- and retinoic-acid-induced reprogramming of DCCs into dormancy suppresses metastasis via restored TGF-β-SMAD4 signaling. Cell Rep 2023; 42:112560. 54▪. Mukherjee A, Bravo-Cordero JJ. Regulation of dormancy during tumor dissemination: the role of the ECM. Cancer Metastasis Rev 2023; 42:99–112. 55▪. Fane ME, Chhabra Y, Alicea GM, et al. Stromal changes in the aged lung induce an emergence from melanoma dormancy. Nature 2022; 606:396–405. 56▪. Aouad P, Zhang Y, De Martino F, et al. Epithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence. Nat Commun 2022; 13:4975. 57. Nobre AR, Dalla E, Yang J, et al. ZFP281 drives a mesenchymal-like dormancy program in early disseminated breast cancer cells that prevents metastatic outgrowth in the lung. Nat Cancer 2022; 3:1165–1180. 58▪. Di Martino JS, Nobre AR, Mondal C, et al. A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy. Nat Cancer 2022; 3:90–107. 59. Correia AL, Guimaraes JC, Auf der Maur P, et al. Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy. Nature 2021; 594:566–571. 60. Tallón de Lara P, Castañón H, Vermeer M, et al. CD39+PD-1+CD8+ T cells mediate metastatic dormancy in breast cancer. Nat Commun 2021; 12:769. 61. Nobre AR, Risson E, Singh DK, et al. Bone marrow NG2+/Nestin+ mesenchymal stem cells drive DTC dormancy via TGFβ2. Nat Cancer 2021; 2:327–339. 62. Kim HS, Kim Y, Lim MJ, et al. The p38-activated ER stress-ATF6α axis mediates cellular senescence. FASEB J 2019; 33:2422–2434. 63. Li B, Huang Y, Ming H, et al. Redox control of the dormant cancer cell life cycle. Cells 2021; 10:2707. 64. Radnaa E, Richardson L, Goldman B, et al. Stress signaler p38 mitogen-activated kinase activation: a cause for concern? Clin Sci (Lond) 2022; 136:1591–1614. 65. Kma L, Baruah TJ. The interplay of ROS and the PI3K/Akt pathway in autophagy regulation. Biotechnol Appl Biochem 2022; 69:248–264. 66. Yuan R, Fan Q, Liang X, et al. Cucurbitacin B inhibits TGF-β1-induced epithelial-mesenchymal transition (EMT) in NSCLC through regulating ROS and PI3K/Akt/mTOR pathways. Chin Med 2022; 17:24. 67. Gu Y, Bui T, Muller WJ. Exploiting mouse models to recapitulate clinical tumor dormancy and recurrence in breast cancer. Endocrinology 2022; 163:bqac055. 68. Recasens A, Munoz L. Targeting cancer cell dormancy. Trends Pharmacol Sci 2019; 40:128–141. 69. Board NL, Moskovljevic M, Wu F, et al. Engaging innate immunity in HIV-1 cure strategies. Nat Rev Immunol 2022; 22:499–512. 70. Carlson P, Dasgupta A, Grzelak CA, et al. Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy. Nat Cell Biol 2019; 21:238–250. 71. Oliveira G, Wu CJ. Dynamics and specificities of T cells in cancer immunotherapy. Nat Rev Cancer 2023; 23:295–316. 72▪▪. Baldominos P, Barbera-Mourelle A, Barreiro O, et al. Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche. Cell 2022; 185:1694–1708. e19. 73▪▪. Hu J, Sánchez-Rivera FJ, Wang Z, et al. STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma. Nature 2023; 616:806–813.