Blocking Cancer–Nerve Crosstalk for Treatment of Metastatic Bone Cancer Pain

The tumor microenvironment is a complex milieu where neurons constitute an important non-neoplastic cell type. From “cancer neuroscience,” the crosstalk between tumors and neurons favors the rapid growth of both, making the cancer–nerve interaction a reciprocally beneficial process. Thus, cancer–nerve crosstalk may provide new targets for therapeutic intervention against cancer and cancer-related symptoms. We proposed a nerve–cancer crosstalk blocking strategy for metastatic bone cancer pain treatment, achieved by Mg/Al layered-double-hydroxide nanoshells (Mg/Al-LDH) with AZ-23 loaded inside and alendronate decorated outside. The pain-causing H⁺ is rapidly eliminated by the LDH, with neurogenesis inhibited by the antagonist AZ-23. As positive feedback, the decreased pain reverses the nerve-to-cancer Ca²⁺ crosstalk-related cell cycle, dramatically inhibiting tumor growth. All experiments confirm the improved pain threshold and enhanced tumor inhibition. The study may inspire multidisciplinary researchers to focus on cancer–nerve crosstalk for treating cancer and accompanied neuropathic diseases.