Neural Innervation of Tumors: Mechanisms, Hallmarks, and Therapeutic Opportunities

Background/Objectives: Increasing evidence indicates that tumors interact functionally with the nervous system. Rather than being passively innervated, many cancers establish bidirectional communication with neurons, suggesting that neural activity may represent an additional regulatory layer of tumor biology. This review aims to synthesize current knowledge on the mechanisms and consequences of tumor innervation and to discuss its implications for cancer progression and therapy. Methods: We performed a narrative synthesis of recent experimental and translational studies (2015–2026), identified through PubMed and major peer-reviewed biomedical journals. The literature was analyzed to identify key mechanisms of neural influence on tumor biology, including axonogenesis, pseudo-synaptic communication, neurotransmitter signaling, and metabolic coupling. Results: Emerging evidence indicates that neural inputs can regulate multiple hallmarks of cancer, including proliferation, invasion, angiogenesis, metabolic plasticity, and immune evasion. Tumors can actively recruit nerve fibers through axonogenic signals and establish specialized neuron–cancer interfaces that enable activity-dependent oncogenic signaling. In addition, neuronal interactions can influence tumor metabolism and therapeutic resistance through mechanisms such as mitochondrial transfer and neurotransmitter-driven signaling pathways. Conclusions: Tumor innervation represents an important and increasingly recognized dimension of cancer biology. Understanding how neural circuits interact with tumor cells and the surrounding microenvironment may reveal new biomarkers and therapeutic strategies aimed at disrupting tumor–neuron communication.