Osteoblasts in bone metastasis: Key players in the tumor microenvironment and therapeutic targets

Osteoblasts, recognized for their role in bone formation and mineral metabolism, are emerging as pivotal, although underexplored, regulators within the bone tumor microenvironment (TME). Despite increasing evidence of their involvement, their precise contributions to metastatic progression remain underappreciated. Recent studies reveal that osteoblasts orchestrate metastasis through dynamic, stage-specific interactions. In early colonization, they may attract tumor cells via CXCL12/CXCR4 signaling and remodel the metastatic niche. During dormancy, osteoblast-derived factors such as LIF, TGFβ2, and BMP7, along with adhesion molecules such as N-cadherin, promote therapy resistance. Subsequently, osteoblasts can drive metastatic outgrowth through metabolic coupling (e.g., Ca²⁺ transfer) and mTOR pathway activation. Beyond these direct effects on tumor cells, osteoblasts modulate the TME by interacting with osteoclasts and immune cells, suppressing CD8⁺ T/NK cell activity while skewing macrophage polarization to promote immune evasion. Tumor-derived signals including PTHrP, BMPs, and ET-1, further reprogram osteoblasts into a tumor-supportive phenotype. Therapeutic approaches, such as RANKL inhibition, CXCL12 pathway blockade, TGF-β superfamily antagonism, and osteoblast-targeted immunotherapies, offer promising directions for clinical intervention. Recognizing osteoblasts as central players in bone metastasis may provide new frontiers in bone-targeted cancer therapy.