Sensory neuro-tumor crosstalk: Therapeutic opportunities and emerging frontiers in cancer neuroscience

Abstract

Emerging evidence in cancer neuroscience highlights the crucial role of sensory nerves in tumor progression, an aspect of cancer pathobiology previously overlooked. Mechanistically, tumor-associated sensory neurons establish a self-reinforcing oncogenic loop via secreted neurotrophic factors (e.g., NGF/BDNF), which directly promote cancer cell growth, spread, and treatment resistance through Trk activation. Concurrently, tumors rewire their local environment through dysregulated expression of axon guidance molecules, facilitating invasive growth. Importantly, nociceptive signaling activated during perineural invasion not only mediates cancer-related pain but also shapes an immunosuppressive microenvironment through neuropeptide-mediated changes in immune cell function. Current therapeutic strategies targeting tumor-associated nerves focus on: (1) Pharmacological blockade of nerve-tumor communication using small-molecule inhibitors (e.g., Trk inhibitor larotrectinib); (2) Bioelectronic modulation of neural activity via modalities such as transcutaneous electrical nerve stimulation. Notably, preclinical models reveal enhanced efficacy when combining neural modulation with immune checkpoint inhibitors. Technological breakthroughs, including single-cell analysis for precise nerve targeting and advanced drug delivery systems, are improving therapeutic precision. Consequently, understanding the complex interactions between nerves and tumors requires integrated approaches combining cancer biology, neuroimmunology, and systems neuroscience. This conceptual shift not only reshapes our understanding of cancer pathophysiology but also opens new avenues for precision therapies aligned with modern oncology.