Neural regulation of tumor progression: implications for hepatocellular carcinoma

The nervous system is increasingly recognized as an active regulator of oncogenesis rather than a passive structural component of the tumor microenvironment (TME). Neural activity promotes tumor proliferation, invasion, metastasis, therapeutic resistance and immune evasion through dynamic, bidirectional interactions with malignant cells and stromal components. These effects are mediated by diverse mechanisms, including synaptic and pseudo-synaptic communication, paracrine release of neurotransmitters and neuropeptides, metabolic reprogramming, and neuro-immune crosstalk. Importantly, tumors do not simply receive neural signals; they actively remodel the peripheral nervous system by inducing axonogenesis and neo-innervation, thereby establishing feed-forward circuits that facilitate disease progression. In hepatocellular carcinoma (HCC), central nervous system responses to systemic stress converge with local hepatic signaling to regulate tumor dynamics. Sympathetic, parasympathetic, and sensory innervation influence hepatocarcinogenesis by modulating inflammation, immunosuppression, stromal remodeling and cellular metabolism. These processes may contribute to the transition from chronic liver disease to malignant transformation. Although recent studies have demonstrated neuro-tumor crosstalk in HCC, critical knowledge gaps remain, including the precise neural circuits involved, the temporal dynamics of innervation during disease progression, and the intersection of these pathways with canonical oncogenic drivers. This review summarizes current knowledge of neural-mediated tumor progression across malignancies and discusses the relevance of these paradigms to HCC, with an emphasis on potential therapeutic vulnerabilities. A deeper mechanistic understanding of these processes is essential for translating neuro-oncological concepts into targeted neuromodulatory therapies for HCC.