Modeling and targeting the hostile physicochemical niche in bone metastasis: from experimental platforms to niche-directed therapy.

Cancer metastasis to bone is shaped not only by tumor-stromal crosstalk but also by a hostile physicochemical niche that promotes disease persistence and therapeutic failure. Hypoxia, acidosis, mineralized matrix architecture, altered mechanics, interstitial pressure, impaired perfusion, and limited drug transport influence metastatic seeding, dormancy, reactivation, remodeling, pain, and treatment response. Conventional two-dimensional cultures and many simplified three-dimensional systems reproduce only selected features of this environment, often overestimating therapeutic efficacy. This review examines experimental platforms designed to model bone metastasis with greater biological and biophysical fidelity, including mineralized scaffolds, multicellular co-cultures, ex vivo bone explants, organoids, bone-on-chip and microphysiological systems (MPS), animal models, and computational or hybrid approaches. Rather than ranking models by complexity, we propose a fit-for-purpose framework in which platform selection is guided by the biological question, the lesion feature being tested, and the required balance between control, scalability, and physiological fidelity. We further discuss how modeling oxygen tension, extracellular pH, pressure, mechanics, vascular transport, immune context, and neural interactions can inform niche-directed therapeutic strategies. The central challenge is to build models that reproduce clinically relevant bone lesion states and thereby improve therapeutic prediction, patient stratification, and treatment design.