Repositioning osteocytes as integrative regulators of breast cancer bone metastasis

Breast cancer bone metastasis remains a major clinical challenge, yet the mechanisms governing metastatic dormancy, reactivation and osteolytic progression within the bone metastatic niche remain incompletely understood. Although the osteoblast-osteoclast 'vicious cycle' has long provided a foundational framework for explaining tumour-induced bone destruction, it does not fully account for several defining features, including prolonged metastatic latency, heterogeneous relapse timing and sensitivity to mechanical and systemic cues. Here, we propose an osteocyte-centred perspective that complements established tumour-bone interaction models by considering osteocytes as integrative regulators of bone niche state. As the most abundant, long-lived and mechanosensitive cells in bone, osteocytes are well positioned to coordinate biomechanical, endocrine, inflammatory and metabolic signals over time. Emerging evidence suggests that osteocyte functional state may influence whether the bone microenvironment remains relatively stable or becomes more permissive for metastatic progression: physiologically intact osteocytes are associated with niche stability and dormancy-supportive conditions, whereas stressed, apoptotic or senescent osteocytes are linked to osteoclast activation, inflammatory remodelling and osteolytic outgrowth. We synthesise recent findings suggesting that osteocytes may participate across multiple stages of bone metastasis, from niche conditioning and dormancy regulation to reactivation and osteolytic progression, through reciprocal crosstalk with tumour cells involving mechanotransduction, cytokine signalling and extracellular vesicle-mediated communication. We also emphasise the current limitations of the evidence base, particularly in relation to pre-metastatic niche formation, organotropism and EV-associated regulatory mechanisms. Rather than displacing existing models, this framework aims to connect mechanobiology, osteoimmunology, endocrine signalling and remodelling dynamics within a stage-aware view of metastatic progression. By repositioning osteocytes as active components of the bone metastatic niche, this review highlights testable concepts for understanding skeletal metastatic dynamics and for informing strategies aimed at stabilising a tumour-restrictive bone microenvironment.