Bridging the Gap in Breast Cancer Dormancy: Models, Mechanisms, and Translational Challenges

Abstract

Breast cancer (BC) poses a significant clinical challenge due to late metastatic recurrence, driven by dormant disseminated tumor cells (DTCs). This review emphasizes the urgency of addressing tumor dormancy to reduce metastatic relapse, a major contributor to BC mortality. DTCs evade conventional therapies and immune surveillance, reactivating unpredictably, thus necessitating targeted strategies. Current research is fragmented, with conflicting data, inadequate models, and a lack of biomarkers hindering progress. This review synthesizes these gaps and proposes actionable priorities, advocating for integrated, standardized approaches. It highlights the roles of single-cell multi-omics, spatial transcriptomics, and humanized long-term models in unraveling dormancy mechanisms. The review also emphasizes macrophage-targeted therapies, dormancy-specific trials, and biomarker validation, offering paths to clinical translation. Ultimately, this work emphasizes the urgent need for integrated multi-omics approaches, including single-cell and spatial transcriptomics, combined with advanced computational analysis. Moreover, this review critically analyzes the existing research landscape, meticulously identifying key gaps, and proposing concrete, forward-looking directions for both fundamental research and clinical translation in the challenging field of BC dormancy.

Keywords: BC; metastatic recurrence; microenvironment; translational research; tumor dormancy.

Figure 1

A comprehensive schematic representation of the dynamic process by which disseminated tumor cells (DTCs) transition from a proliferative TME to a dormant niche, highlighting the key stages of intravasation, dissemination, extravasation, and niche adaptation. The figure begins in the top left corner with the tumor microenvironment, where cancer cells undergo cell cycle progression driven by cyclin-dependent kinase (CDK) activity, resulting in a proliferative TME. The TME is enriched with migratory cytokines, facilitating epithelial-mesenchymal transition (EMT), invasion, and eventual metastasis. CAFs, red blood cells (RBCs), quiescent cells, bone morphogenetic proteins (BMPs), growth factors (GFs), fibronectin, collagen, laminin, and osteoblasts are illustrated as critical components within the TME. Tumor cells then intravasate into the bloodstream, becoming circulating tumor cells (CTCs), which can disseminate to distant organs. Once in circulation, DTCs encounter a non-permissive environment that impedes immediate colonization. Some DTCs retain active CDK signaling, while others undergo immune suppression and therapeutic resistance. As DTCs reach secondary sites, they may extravasate into local tissue, where microenvironmental factors determine their fate. The bottom left quadrant shows the establishment of a pro-metastatic niche characterized by an abundance of CAFs and elevated levels of interleukins IL-1, IL-2, and IL-6, as indicated by arrows marking their local secretion. This niche supports DTC proliferation and is rich in ECM components such as fibronectin and laminin, as well as an active chromatin structure that allows for transcriptional activity, promoting tumor growth and colonization. The bottom right quadrant contrasts this with a dormant niche, where the microenvironment favors DTC quiescence. Here, ECM components like laminin and fibronectin, along with interactions with osteoblasts, contribute to cellular dormancy. The chromatin in these cells is likely inactive or condensed, and signaling pathways are less conducive to proliferation. The entire process is modulated over time by aging, as shown by the downward arrow from the pro-metastatic niche to the dormant niche, suggesting that age-related changes in the ECM, cytokine levels, and stromal composition contribute to the shift from a proliferative to a dormant state. Created by BioRender (https://www.biorender.com).

Figure 2

Dynamic modulation of the TME governing cancer cell dormancy versus proliferation. This two-panel schematic illustrates the distinct molecular and cellular landscapes that dictate either the reawakening/proliferation or dormancy/quiescence of cancer cells within the metastatic niche. In the upper panel (“Proliferation/Reawakening”), the TME supports metastatic outgrowth through active interactions between cancer cells, stromal components, and immune cells. Pro-growth factors including PDGF, FGF, WNT, VCAM, and NOTCH, along with transcriptional regulators like OCT4 and FAK, are secreted by stromal and endothelial cells, while fibroblasts and extracellular matrix (ECM) components such as fibronectin, type I collagen, osteopontin, and tetraspanins facilitate cell adhesion, survival, and invasion. Inflammatory cytokines such as IL-6 and IL-23, together with neutrophil extracellular traps (NETs), further stimulate cancer proliferation and immune evasion. Conversely, the lower panel (“Dormancy/Quiescence”) portrays a suppressive TME enriched with dormancy-inducing signals. Bone morphogenetic protein 7 (BMP7), TGF-β, and exosomes derived from stromal cells, in concert with immune-regulatory cytokines like IL-12 and IFN-γ, contribute to a non-proliferative state. Anti-angiogenic factors including angiostatin, endostatin, and integrin-β help prevent neovascularization, maintaining cancer cells in a latent, non-dividing condition. This balance between proliferative signaling and dormancy cues is tightly controlled by the spatial and temporal orchestration of CAFs, immune infiltrates, and ECM remodeling, with CAFs emerging as key modulators. They can either promote reawakening through the secretion of proliferative cytokines and matrix proteins or support dormancy via TGF-β and exosomal communication, making them central targets in preventing cancer recurrence and metastasis. Created by BioRender.

Figure 3

Molecular and microenvironmental pathways regulating breast cancer dormancy. This figure illustrates the major interconnected mechanisms underlying the maintenance and reactivation of dormant breast cancer cells. (1) The angiogenic switch is tightly regulated by pro- and anti-angiogenic factors; Thrombospondin-1 (TSP-1) inhibits angiogenesis and supports dormancy, while VEGF (vascular endothelial growth factor) promotes neovascularization and enables outgrowth of dormant tumor cells near blood vessels. (2) Immune surveillance plays a dual role—T cells and NK cells can either sustain dormancy or mediate reawakening through cytokines such as IL-2 and TNF; the expression of MHC-I on tumor cells modulates recognition and immune editing. (3) Cellular stress responses such as the unfolded protein response (UPR) are activated by ER stress and influence dormancy via the balance between p38 MAPK and ERK1/2 MAPK pathways; a low ERK\:p38 ratio favors entry into a dormant state. (4) The tumor microenvironment (TME), especially cancer-associated fibroblasts (CAFs), contributes to dormancy or reactivation via secreted factors, epigenetic remodeling, ECM alterations, reactive oxygen species (ROS) production, and metabolic reprogramming. (5) Autophagy and metabolic adaptation, particularly mitophagy mediated by the PINK1/PARKIN axis and autophagy-related components like LC3 and Beclin1, support cell survival under nutrient deprivation and stress, enabling long-term tumor cell quiescence. These interconnected pathways collectively define the dormancy landscape and represent targets for therapeutic intervention to prevent metastatic relapse. Created by BioRender.

Figure 4

Mechanisms of CAF activation, recruitment, and contribution to tumor progression and immune evasion. This schematic illustrates the dynamic TME and the complex interplay of cellular and molecular events that lead to the activation of CAFs and their contribution to cancer growth and progression. Various cell types including endothelial cells, pericytes, monocytes, MSCs, quiescent pancreatic stellate cells (qPSCs), mesothelial cells, adipocytes, and epithelial cells can be recruited and reprogrammed into CAFs through diverse signaling pathways such as PDGF-β/PDGFR-β (pericytes), EndMT (endothelial-mesenchymal transition), EMT (epithelial-mesenchymal transition), and MMT (mesothelial-mesenchymal transition), often driven by the tumor-secreted factors including CXCL12, TGF-β, and oxidative stress. CAFs localize around tumor nests and blood vessels, interacting with cancer cells, macrophages, and immune cells to modulate tumor behavior. They contribute to immune evasion by regulating immune checkpoints such as the PD-1/PD-L1 axis and suppressing T cell activation, while also promoting an immunosuppressive environment through secretion of exosomal miRNAs such as miR-92, miR-203, miR-212 (targeting NK cells), and miR-210, miR-23a (targeting dendritic cells). These exosomal miRNAs further impair anti-tumor immunity and promote tumor immune escape. In parallel, CAFs enhance cancer cell proliferation and resistance through the secretion of soluble factors and extracellular vesicles that modulate non-sensitive fibroblasts (NFS), converting them into tumor-promoting phenotypes via miR-31, and by regulating miR-1 and miR-206 to sustain survival and adaptation of resistant cancer cells. Overall, CAFs orchestrate a multifaceted network that fuels tumor cell proliferation, enhances stemness, drives therapy resistance, and reshapes the immune microenvironment, establishing themselves as central mediators of cancer progression and critical targets for anti-cancer therapy. Created by BioRender.

Figure 5

A comprehensive overview of how microfluidic devices are used to replicate the TME and simulate the complex interplay of physical and biochemical factors that influence tumor development, progression, and metastasis. The upper portion illustrates a vascularized tissue interface, where circulating tumor cells (CTCs) within blood vessels interact with endothelial cells, adhere to vessel walls, and undergo extravasation into the surrounding tissue under the influence of chemokines, cytokines, and mechanical shear forces. The TME is composed of immune cells such as macrophages and lymphocytes, tumor-associated fibroblasts, extracellular matrix (ECM), and tissue-derived stromal cells, all of which contribute to the modulation of tumor behavior and metastatic potential. These cellular and molecular components create a niche that supports cancer cell invasion and colonization at distant organs. The lower portion of the figure zooms into a microfluidic chip that mimics this vascularized environment, enabling high-resolution, in vitro modeling of cancer cell extravasation. This model captures critical TME features such as intercellular communication, cell-ECM interactions, and hypoxic gradients, which are essential for understanding tumor physiology. The chip also allows the reproduction of biochemical gradients like oxygen levels and the formation of vascular-like networks, simulating tumor angiogenesis. Overall, the microfluidic platform provides a dynamic and tunable environment to study tumor cell behavior under physiologically relevant conditions, including mechanical shear stress, hypoxia, vascularization, and stromal interactions, making it a powerful tool for cancer research, therapeutic testing, and personalized medicine development. Created by BioRender.