The Neuro-Bone Axis in Metastatic Progression: Innervation, Neuro-Immune-Osteoclast Crosstalk, and Therapeutic Opportunities.

Bone metastases represent a major cause of morbidity in advanced cancers, yet the neural regulation of metastatic growth within bone remains largely unexplored. The skeletal system is richly innervated by sensory and sympathetic nerve fibers that influence bone remodeling, hematopoiesis, and immune surveillance. Emerging evidence suggests that disseminated tumor cells exploit these neural circuits to create a growth-permissive microenvironment. Tumor-secreted neurotrophic factors can induce nerve sprouting, while sympathetic activation via β-adrenergic receptors promotes osteoclastogenesis, immunosuppression, and tumor proliferation. Neuropeptides such as substance P and calcitonin gene-related peptide exert dual effects on bone cells and infiltrating immune populations, further shaping the metastatic niche. The interplay between neural signals, osteolytic activity, and immune modulation positions the neuro-bone axis as a critical but underappreciated driver of metastatic progression. In this review, we synthesize current evidence on the anatomy and function of bone innervation, tumor-induced neural remodeling, and neuro-immune-osteoclast interactions. We highlight preclinical and clinical data supporting neuromodulatory strategies, including β-blockers, neurotrophin inhibitors, and targeted nerve ablation, as potential adjuncts to standard bone metastasis therapies. Finally, we identify key knowledge gaps, including the need for spatial and functional mapping of nerve-tumor interfaces and for integrating neuroimaging into bone metastasis detection. By framing the neuro-bone axis as a therapeutic target, we aim to catalyze interdisciplinary research that bridges oncology, neuroscience, and bone biology, with the goal of disrupting neural support for metastatic growth.