Perineural invasion in hepatocellular carcinoma: clinical evidence and mechanistic hypotheses

Hepatocellular carcinoma (HCC) is a major cause of cancer mortality worldwide. Emerging evidence in cancer neuroscience suggests that tumor–nerve crosstalk can modulate tumor growth, immune remodeling, dissemination, and therapy resistance. Perineural invasion (PNI) is a hallmark of aggressive tumors and correlates with recurrence, metastasis, disease-specific death, and neuropathic pain, yet its prevalence and prognostic relevance in primary HCC remain inconsistently defined. Given the limited and heterogeneous clinical data, we synthesize available observations and propose mechanistic hypotheses for neural–tumor interactions in the hepatic niche. Potential drivers are organized into five domains—neurotrophic factors, axon guidance molecules, neurotransmitter signaling, cell adhesion molecules, and the tumor microenvironment—highlighting neuro–immune–stromal circuits that may create permissive perineural niches. We also outline experimental platforms to test these hypotheses, including co-culture systems, organoids, and microfluidic nerve-on-chip models. Targeting neural–tumor interactions may offer translational opportunities in HCC, but causality and actionable targets cannot be established without improved clinical and experimental rigor. Standardized pathological assessment and dedicated HCC-focused PNI models are needed to validate mechanisms, harmonize reporting, and enable reproducible, clinically meaningful advances.