Unraveling the role of perineural invasion in cancer-associated pain: Insights and treatment strategies

• Perineural invasion (PNI) contributes to metastasis, recurrence, and reduced survival. • Tumor-neural interactions via neurotrophic factors and immune responses drive PNI. • Tumor-nerve interactions via neurotrophins, inflammation, and immune signals drive PNI pain. • Targeted therapies disrupting tumor-nerve interactions may improve cancer pain management. Perineural invasion (PNI) occurs when cancer cells infiltrate the space around nerves, commonly seen in head and neck, pancreatic, prostate, and colorectal cancers. PNI is clinically significant as it promotes metastasis, recurrence, and reduced survival. Mechanistically, it involves tumor-neural microenvironment interactions mediated by neurotrophic factors, inflammatory signals, and immune responses. PNI also causes severe neuropathic pain due to nerve compression, plasticity, and inflammation, resulting in sensory abnormalities from neuronal hyperexcitability, demyelination, and upregulated ion channels. This pain significantly impacts quality of life and complicates cancer management. Cells like macrophages and Schwann cells amplify pain via paracrine signaling and pro-inflammatory mediators. Standard pain management, including NSAIDs and opioids, often fails due to toxicity. Emerging therapies target PNI-specific mechanisms to limit tumor-nerve interactions and relieve pain. Research focuses on improving PNI models, dissecting tumor neuroimmune networks, and translating targeted therapies for effective pain relief.