REVIEW article
Front. Cell Dev. Biol.
Sec. Cancer Cell Biology
The Neural Niche in Cancer: Mechanistic Insights into Tumor–Neuron–Immune Crosstalk and Therapeutic Opportunities
Provisionally accepted
- 1Department of Oncology, Karmanos cancer Institute, School of Medicine, Wayne State University, Detroit, United States
- 2Wayne State University, Detroit, United States
- 3Department of Physiology, Regenerative and Restorative Research Center (REMER), Istanbul Medipol Universitesi Uluslararasi Tip Fakultesi, Beykoz, Türkiye
- 4Department of Physiology, Bolu Abant Izzet Baysal Universitesi Tip Fakultesi, Bolu, Türkiye
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The nervous system is increasingly recognized as a dynamic and regulatory component of the tumor microenvironment (TME), 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, CGRP) that influence not only tumor growth, angiogenesis but also immune cell polarization, T cell exhaustion, dendritic cell maturation and myeloid-derived suppressor cell (MDSC) 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 (SAM) 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.
Keywords: adrenergic signaling, cancer-neuron-immune axis, neurotransmitters, neurotrophic factors, Perineural invasion, Tumor innervation, Tumor Microenvironment
Received: 18 Jul 2025; Accepted: 12 Feb 2026.
Copyright: © 2026 Korkaya, Ayşit, Altintas, Alkan and Ozturk. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Hasan Korkaya
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