Introduction
Neural regulation of tumor growth
When tumors rewire the brain and nerves
The neural routes that enable cancer metastasis
Targeting communication between tumors and nerves
A new era of cancer neuroscience
References
Further reading
Tumors do more than coexist with nerves; they can recruit, rewire, and exploit neural signaling in ways that reshape growth, immunity, and metastatic spread.
Image Credit: Kateryna Kon / Shutterstock.com
Introduction
Recent evidence shows a complex bidirectional relationship between the nervous system and cancer. This emerging field, known as cancer neuroscience, examines how neurons, neurotransmitters, and neural networks influence tumor initiation, growth, immune regulation, and metastasis, while tumors actively remodel and recruit neural structures to support their progression. These interactions can occur locally within the tumor microenvironment or systemically through neural, neuroendocrine, neuroimmune, and circulating signaling pathways. Understanding these complex interactions has transformed perspectives on tumor biology and identified the nervous system as a promising target for novel cancer therapies.1,3,5
Neural regulation of tumor growth
The nervous system regulates tumor growth through a complex network of signaling molecules, neural pathways, and direct interactions with the tumor microenvironment. Neurotransmitters like dopamine, glutamate, serotonin, and gamma-aminobutyric acid (GABA) act on receptor sites located on both tumor and stromal tissues and can exert highly context-dependent effects. Many neural signaling pathways promote cell proliferation, migration, invasion, angiogenesis, immune suppression, and resistance to cell death, whereas particular neurotransmitters, receptors, or nerve populations can have inhibitory effects in specific tumor types.1,4,5 Tumor cells also release factors like brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) that promote neural growth, thereby facilitating communication between cancer cells and the nervous system.1,2,4
Chronic stress activates the hypothalamic-pituitary-adrenal axis and the sympathoadrenal system, leading to the release of catecholamines such as epinephrine and norepinephrine. Catecholamines activate β-adrenergic receptors on both cancerous and non-cancerous cells within the tumor microenvironment, stimulating pathways that promote tumor growth and angiogenesis, as well as immune evasion and metastasis. Blocking adrenergic signaling has been shown to inhibit tumor growth and progression in multiple preclinical cancer models, thus exemplifying the role of neural regulation in the development of malignancy.1,3,4
Tumors can promote nerve growth by secreting neurotrophic factors, axon-guidance signals, and extracellular vesicles, thereby creating a reciprocal signaling network. This neural remodeling supports tumor development by fostering a microenvironment that favors proliferation, survival, and dissemination, making neural innervation an increasingly recognized hallmark of cancer.3,4,5 Importantly, different nerve populations can exert opposing effects: sympathetic signaling is frequently tumor-promoting, whereas parasympathetic or sensory pathways can restrain progression in particular cancers, including experimental models of pancreatic cancer and melanoma.4,5
Neural signals also remodel anti-tumor immunity by influencing macrophages, natural killer cells, myeloid cells, and T lymphocytes. Depending on the pathway and cancer type, this neuroimmune crosstalk can promote immunosuppression and T-cell exhaustion or enhance anti-tumor immune activity.1,4,5
What is Cancer Neuroscience?
When tumors rewire the brain and nerves
Cancer cells can acquire or co-opt sophisticated mechanisms to promote their survival and expansion. For example, cancer-induced neuroplasticity is characterized by neurogenesis and the release of neurotrophic factors such as NGF and BDNF, which promote the growth of new nerve fibers into the tumor microenvironment, increasing nerve density and strengthening nerve-cancer cell communication. The resulting feedback loop enables the continued delivery of pro-tumorigenic signals to the tumor while simultaneously promoting further nerve infiltration into the tumor.3,4,5 In some cancers, communication is even more direct: glioma cells can form functional synaptic connections with neurons, while breast cancer cells that have metastasized to the brain can exploit neuronal glutamatergic signaling through pseudo-tripartite synaptic structures, promoting growth at metastatic sites.4,5
Cognitive and emotional dysfunction, as well as fatigue and behavioral changes, are prevalent among cancer patients, even in the absence of brain metastases. The causes are multifactorial and may include cancer treatment, fatigue, chronic stress, endocrine and immune disturbances, paraneoplastic effects, direct or metastatic tumor involvement, and systemic communication between peripheral tumors and the central nervous system. Neuroinflammatory signaling is one proposed contributor rather than a single established explanation for these symptoms.1,5
During perineural invasion, tumor cells invade and spread within, around, or along nerves, providing a distinct route of local and regional cancer dissemination and contributing to pain and recurrence in several malignancies.2,5 Neurotrophic factors like NGF, BDNF, and glial cell line-derived neurotrophic factor (GDNF) similarly guide cancer cells toward neural tissues, facilitating their invasion of the perineural space.2,4,5 Although perineural invasion is associated with adverse outcomes in cancers including pancreatic, colorectal, gastric, and oral cancers, its prognostic significance is tumor-type dependent and is not uniform across all malignancies.2
Nerves infiltrate tumors to release neurotransmitters and neuropeptides that enhance tumor cell migration, angiogenesis, and anti-apoptotic activity. Neural signaling can also influence immune cells and stromal components, further intensifying a pro-metastatic environment.3,4,5
Tumor innervation and axonogenesis are associated with aggressive tumor behavior and can reinforce metastatic processes through neural regulation of angiogenesis, cancer-cell survival, migration, and immune function.1,2,4,5 Chronic stimulation of adrenergic receptors by chronic stress can alter the expression of proteins involved in epithelial-mesenchymal transitions and vasculature remodeling to similarly promote metastasis.4,5
Image Credit: viktorov.pro / Shutterstock.com
Targeting communication between tumors and nerves
Disrupting communication between cancer cells and the nervous system has been investigated through various approaches, including the inhibition of receptors, neurotrophins, and other signaling molecules implicated in tumor growth. Beta-blockers, for example, inhibit β-adrenergic signaling induced by epinephrine and norepinephrine activity. Preclinical studies show that inhibiting adrenergic signaling can reduce tumor growth, angiogenesis, metastatic behavior, immunosuppression, and treatment resistance across several experimental settings. Clinical studies and trials of beta-adrenergic antagonists, including their combination with conventional and immune-based therapies, are ongoing; however, a broadly applicable anticancer benefit in patients has not yet been established.1,4,5
Emerging strategies include targeting neurotrophic signaling pathways, inhibiting tumor-induced nerve growth, modulating neuroimmune interactions, and disrupting perineural invasion. Recent advances in cancer neuroscience may lead to personalized treatment options that combine oncology, neuroscience, and immunology by targeting neuro-related aspects of the tumor microenvironment to improve treatment outcomes and reduce the risk of recurrence and metastasis.5 A major challenge is achieving tumor-selective neuromodulation without disrupting the physiological functions of the nervous system; inhibition of pathways such as NGF or BDNF signaling can potentially produce neurological, sensory, or neuropsychiatric adverse effects.4,5
A new era of cancer neuroscience
Advanced imaging technologies, molecular profiling, and single-cell methodologies are providing new insights into how neural circuits affect the initiation, progression, and metastasis of cancer. Integrating neuroscience into oncology will provide a more comprehensive understanding of cancer as a systemic disease involving neural, immune, and metabolic pathways.3 Emerging frameworks also extend this concept to the gut-brain-immune axis and interactions between the nervous system, microbiota, immunity, and cancer.5 As knowledge of nerve-tumor communication expands, combining neurological and oncological approaches may lead to improved biological stratification, prognostic approaches, and therapies directed at specific neural components of the tumor microenvironment.1,3,5 Despite rapid progress, much of the mechanistic evidence remains derived from cell and animal models, and translating neural targets into safe, effective cancer treatments remains an important challenge for the field.4,5
References
- Huang, Q., Hu, B., Zhang, P., et al. (2025). Neuroscience of cancer: unraveling the complex interplay between the nervous system, the tumor, and the tumor immune microenvironment. Molecular Cancer 24(1). DOI: 10.1186/s12943-024-02219-0. https://link.springer.com/article/10.1186/s12943-024-02219-0
- Kuol, N., Stojanovska, L., Apostolopoulos, V., & Nurgali, K. (2018). Role of the nervous system in cancer metastasis. Journal of Experimental & Clinical Cancer Research 37. DOI: 10.1186/s13046-018-0674-x. https://link.springer.com/article/10.1186/s13046-018-0674-x
- Magnon, C., & Hondermarck, H. (2023). The neural addiction of cancer. Nature Reviews Cancer 23(5); 317-334. DOI: 10.1038/s41568-023-00556-8. https://www.nature.com/articles/s41568-023-00556-8
- Zhang, Y., Liao, Q., Wen, X., et al. (2025). Hijacking of the nervous system in cancer: mechanism and therapeutic targets. Molecular Cancer 24(1). DOI: 10.1186/s12943-025-02246-5. https://link.springer.com/article/10.1186/s12943-025-02246-5
- Wang, T., Dong, Z., Wang, Y., et al. (2026). Cancer Neuroscience: Innovative Conception and Emerging Strategy of Therapy. MedComm 7(4). DOI: 10.1002/mco2.70708. https://onlinelibrary.wiley.com/doi/10.1002/mco2.70708
Further Reading
Last Updated: Aug 19, 2026