Curatively resected solid cancers often relapse with distant metastasis (the bone being among the preferred sites), despite systemic administration of molecularly tailored (neo)adjuvant or chemo-therapies. Outgrowth of tumor cells disseminated to secondary organs might not occur instantly, with recurrences ranging from years to decades, pointing to the fact that a number of these cells might go into a drug-resistant state of dormancy. The rarity and complexity associated with detection, isolation and analysis of disseminated tumor cells (DTCs) in disease-free patients have called for an urgent need to develop in vitro culture systems to artificially mimic this asymptomatic state of cancer metastasis, therefore enabling scalable drug screening campaigns to identify drugs able to target DTCs. Recent studies have found dense extracellular matrix (ECM) confining individual disseminated cancer cells, hinting to ECM-mediated mechanical confinement to be a plausible mechanism inducing cancer dormancy. Here we engineered a quiescence-inducing three-dimensional (3D) engineered matrix using ultraviolet (UV) light-initiated covalently-crosslinked thiol-ene alginate hydrogels, which generates mechanical confinement inducing growth arrest of weakly and highly metastatic breast cancer cell lines. After extensive material characterization of the engineered platform, as well as thorough phenotypic profiling (i.e. viability, metabolic activity, cell cycle state, proliferation, drug sensitivity) of the encapsulated cells, we looked at the biophysical properties of these growth-arrested cells with state-of-the-art contact/label-free techniques. Specifically, we quantitatively mapped the 3D mass density distribution of encapsulated human breast cancer cells (BCCs) MDA-MB-231, using a combined optical diffraction tomography (ODT)-epifluorescence microscope. We then mapped the 3D viscoelastic properties of these cells via Brillouin spectroscopy. Surprisingly, and in contrast to cells adhering to 2D substrates, the nuclei of cells in 3D revealed a higher mass density, as well as higher stiffness and viscosity compared to the cytoplasm. Next, we moved to a more molecular characterization (i.e. immunostaining of selected molecules, RNA seq) of growth-arrested cells. We showed that our artificial quiescence-inducing matrix selects for distinct populations of growth-arrested cells, with cells in the G0/G1 cell cycle phase being more resistant to confinement. Combined with RNA sequencing, we revealed a stiffness-dependent nuclear localization of the four-and-a-half LIM domains 2 (FHL2) protein as an underlying mechanism of quiescence, which led to a p53-independent p21Cip1/Waf1 expression, validated in human and murine tissue. Suggestive of a resistance-causing role, quiescent cells became sensitive against drug treatment upon FHL2 downregulation, evidencing the potential of our approach as a tool for the identification and targeting screens for novel compounds suited to eradicate potentially relapsing DTCs. Finally, we sought to observe how DTCs behave in the bone in a more physiologically relevant system. Building on a growing body of evidence suggesting the existence of parallels between DTCs and quiescent hematopoietic and progenitor stem cells (HSPCs), we seeded DTCs within a 3D hydroxyapatite-coated zirconium oxide scaffold pre-seeded with primary human mesenchymal stromal cells (MSCs) and human cord blood-derived multipotent HSPCs. Interestingly, we detected BCCs and HSPCs entrapped in a web-like network of fibronectin, with BCCs leaning towards a slow-proliferative state, hinting at a potential quiescence-inducing role for the bone microenvironment. Despite the inherent complexities associated with the molecular characterization of biological processes, viewing these phenomena from a physical perspective allows for a more global description, independent from many details of the systems. By drawing parallels with clinical and experimental data, and building on thermodynamic phase separation concepts, we classified microenvironmental-mediated dormancy mechanisms in terms of nucleation processes based on three distinct classes of interactions: (i) cells adhering to a wetting flat surface in the form of a spherical cap (ii) a spherical droplet enclosed by an elastic sheath as a mechanical interpretation of extracellular matrix (ECM)-mediated confinement, and (iii) a spherical droplet with size-dependent limited growth due to lack of nutrients and oxygen, leading to cell apoptosis deep inside the tissue. We then advance the notion that local energy minima, or metastable states, emerging in the tissue droplet growth kinetics can be considered proxies of dormant states. Despite its simplicity, the provided framework captures several aspects associated with cancer dormancy and tumor growth.