# The neural niche in cancer: mechanistic insights into tumor–neuron–immune crosstalk and therapeutic opportunities

## TL;DR

This review explores how nerves, tumors, and immune cells interact, revealing new therapeutic opportunities for cancer treatment.

## Contribution

The paper introduces the concept of a 'neural niche' and highlights mechanistic tumor-neuron-immune crosstalk for therapeutic targeting.

## Key findings

- Tumor cells attract nerves by secreting neurotrophic factors like NGF and BDNF.
- Nerves influence immune cells, promoting tumor growth and immune suppression.
- Perineural invasion correlates with poor prognosis and tumor recurrence.

## Abstract

The nervous system is increasingly recognized as a dynamic and regulatory component of the tumor microenvironment playing critical roles in cancer initiation, progression, metastasis, and resistance to therapy. Recent evidence in cancer neuroscience have revealed a specialized “neural niche” a microanatomical and functional domain enriched in neural inputs and neuromodulatory signals orchestrated through bidirectional communication between tumor, nervus system and immune cellsCancer cells secrete neurotrophic factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) to attract and remodel peripheral innervation. Infiltrating nerve fibers, in turn, release neurotransmitters (e.g., norepinephrine, acetylcholine) and neuropeptides (e.g., substance P, calcitonin gene-related peptide) that influence not only tumor growth, angiogenesis but also immune cell polarization, T cell exhaustion, dendritic cell maturation and myeloid derived suppressor cell recruitment. This neural-immune crosstalk establishes immune suppressive microenvironment that facilitates tumor immune escape and leading to metastatic progression. Perineural invasion (PNI), a distinct pathological process of tumor dissemination, further exemplifies neuroepithelial integration and correlates with recurrence, pain and poor prognosis across multiple solid tumors. Beyond local interactions, chronic stress and systemic neuroendocrine activation via the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic-adrenal-medullary networks, contribute to tumor-promoting immunosuppression through glucocorticoid signaling and sympathetic responses. In this review, we discuss mechanistically integrated and clinical relevant synthesis of tumor-neuron-immune interactions. We emphasize recent conceptual advances, including autonomic balance, systemic neuroendocrine feedback and therapeutic strategies targeting this axis. These insights establish a framework for future translational research and development of neuromodulatory therapies that complement immunotherapy as well as conventional therapeutics.