The regulatory networks and mechanisms of bone microenvironment in tumorigenesis and metastasis.

Bone tumors, encompassing heterogeneous primary and metastatic lesions, are driven in their initiation, progression, and metastasis by dysregulation of the bone microenvironment (BME). Clinically manifested by localized pain, pathological fractures, and neurological deficits, these malignancies substantially threaten patient survival. Radiographic patterns (osteolytic, osteoblastic, mixed) directly reflect pathogenic BME-tumor interactions, particularly involving osteoblast-osteoclast imbalance. The BME-a specialized niche of bone-resident cells (osteocytes, osteoblasts, osteoclasts), immune cells, extracellular matrix, and bioactive factors (e.g., cytokines, growth factors)-orchestrates skeletal homeostasis physiologically, yet its dysregulation drives tumorigenesis and metastatic colonization via three interconnected axes: (1) Cellular dynamics (osteocyte senescence, immune evasion); (2) Matrix remodeling (imbalance between osteolytic and osteoblastic activity); (3) Signaling disruption (abnormal cytokine and growth factor signaling). While BME-directed therapies (e.g., receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors, C-X-C chemokine receptor type 4(CXCR4) antagonists) show promise in disrupting tumor-supportive niches, their off-target effects on healthy bone (e.g., osteonecrosis, impaired fracture healing) pose significant clinical challenges. This review systematically synthesizes: BME composition and tumor-induced reprogramming, Mechanistic roles in metastasis and treatment resistance, Emerging targeted therapies and translational trade-offs. By positioning the BME as both a pathogenic driver and therapeutic vulnerability, we aim to inform future strategies for tissue-specific microenvironmental targeting in bone malignancies.