Tumor-nerve crosstalk: peripheral mechanisms mediating bone tumor progression and cancer-induced bone pain

Cancer-induced bone pain (CIBP) is one of the most debilitating complications of primary bone tumors and bone metastases. Traditionally regarded as a consequence of bone destruction and mechanical compression, CIBP is now recognized as a complex pathological process involving dynamic interactions among tumor cells, peripheral nerves, immune cells, and the bone microenvironment. Increasing evidence indicates that tumor-nerve crosstalk contributes not only to nociceptive sensitization and neural remodeling but also to tumor progression and immune regulation. In the bone tumor microenvironment, tumor-derived mediators, including inflammatory cytokines, neurotrophic factors, and acidic metabolites, activate and sensitize intraosseous nociceptors, promoting peripheral sensitization and pathological nerve sprouting. Conversely, neural components can shape the tumor microenvironment through neurotransmitter signaling, immune modulation, and stromal remodeling and, in selected experimental models, influence tumor growth and metastatic adaptation. Recent advances in cancer neuroscience have further expanded this concept beyond classical biochemical communication. Emerging studies indicate that cancer cells can acquire neuron-derived mitochondria, with tunneling nanotube-like structures implicated in experimental coculture systems. Although this process may enhance tumor metabolic adaptation, its relevance to neural dysfunction and CIBP remains unclear. This review summarizes current evidence regarding the peripheral mechanisms of tumor-nerve interactions in CIBP, with particular emphasis on neural remodeling, neuro-immune communication, mitochondrial transfer, and emerging therapeutic targets. We distinguish established CIBP mechanisms from model-dependent observations and untested hypotheses and discuss the translational limitations of targeting the tumor-bone-nerve interface. This evidence-based distinction may facilitate the development of mechanism-based interventions that alleviate pain without overstating their anticipated effects on tumor progression.