Targeting tumor innervation: premises, promises, and challenges

A high intratumoral nerve density is correlated with poor survival, high metastasis, and high recurrence across multiple solid tumor types. Recent research has revealed that cancer cells release diverse neurotrophic factors and exosomes to promote tumor innervation, in addition, infiltrating nerves can also mediate multiple tumor biological processes via exosomes and neurotransmitters. In this review, through seminal studies establishing tumor innervation, we discuss the communication between peripheral nerves and tumor cells in the tumor microenvironment (TME), and revealed the nerve-tumor regulation mechanisms on oncogenic process, angiogenesis, lymphangiogenesis, and immunity. Finally, we discussed the promising directions of ‘old drugs newly used’ to target TME communication and clarified a new line to prevent tumor malignant capacity.