Neuro-Immune Interactions in Cancer: Emerging Therapeutic Strategies Target the Neural Addiction of Tumors
Key Insights
The nervous system actively regulates tumor immunity through neurotransmitters, cytokines, and neurotrophic factors that shape an immunosuppressive tumor microenvironment.
Beta-blockers like propranolol are being investigated in clinical trials to enhance immune checkpoint blockade efficacy by disrupting stress-induced immunosuppressive pathways.
Preclinical evidence shows that surgical or pharmacological denervation and neurotransmitter pathway targeting can suppress tumor progression across multiple cancer types.
The interplay between the nervous and immune systems has emerged as a fundamental regulator of cancer progression, with mounting evidence demonstrating that tumors actively hijack neural circuits to fuel their own growth—a phenomenon researchers now describe as the "neural addiction of cancer." A comprehensive review published in Frontiers in Immunology synthesizes recent advances in understanding how neuro-immune interactions shape the tumor microenvironment (TME) and highlights promising therapeutic strategies that target these pathways.
The review, authored by Li and colleagues, draws upon a decade of research to delineate the molecular mechanisms, regulatory pathways, and translational applications of the neuro-immune axis across multiple cancer types. "The neuro-immune axis has emerged as a fundamental regulator of cancer progression and therapeutic responsiveness," the authors conclude, noting that tumor-associated neural infiltration and neurotransmitter release actively reshape the TME by promoting immunosuppressive signaling pathways.
Molecular Mechanisms Driving Neuro-Immune Crosstalk
At the molecular level, the dialogue between the nervous and immune systems within tumors is orchestrated by three major classes of signaling molecules: neurotransmitters, cytokines, and neurotrophic factors. These act as bidirectional signaling agents, allowing neurons to modulate immune cell activity while enabling immune cells to influence neural function.
In non-small cell lung cancer (search) (NSCLC), research has demonstrated that nerve growth factor (NGF) drives neural infiltration into tumors, leading to significantly elevated levels of 5-hydroxytryptamine (5-HT, serotonin). This nerve-secreted 5-HT enhances glycolysis in NSCLC cells through activation of the PI3K/Akt/mTOR pathway, a metabolic reprogramming event critical for tumor growth. Critically, this metabolic shift contributes to an immunosuppressive microenvironment by impairing cytotoxic CD8+ T-cell activity, promoting regulatory T-cell expansion, and enhancing secretion of immunosuppressive cytokines such as IL-10 and TGF-β (search). Zheng Y et al. demonstrated that neutralizing 5-HT-mediated metabolic reprogramming could enhance the efficacy of PD-1 (search) monoclonal antibody treatment in murine models.
Neuropeptides also play significant roles. Substance P, released by nociceptor neurons, binds to the neurokinin 1 receptor (NK1R (search)) on breast cancer (search) cells, promoting proliferation and lymph node metastasis. Padmanaban V et al. revealed that Substance P from neurons stimulates growth, invasion, and metastasis of breast cancer, with tumors showing higher Substance P levels exhibiting increased lymph node metastasis.
In colorectal cancer (search), a β2-adrenergic receptor (ADRB2 (search))-NGF feedforward signaling circuit between sympathetic nerves and cancer-associated fibroblasts (CAFs) has been identified. Norepinephrine stimulates ADRB2-dependent NGF secretion from CAFs, enhancing intratumoral sympathetic innervation and establishing a self-amplifying neuro-mesenchymal interaction. Interruption of this signaling axis using TRK inhibitors attenuated YAP and AKT activation and suppressed CRC progression in preclinical models.
Peripheral, Central, and Enteric Nervous System Regulation
The peripheral nervous system (PNS) directly innervates many solid tumors, establishing a direct conduit for neuro-immune communication. Sympathetic nerve signaling predominantly promotes tumor progression by rewiring the TME toward tumor-supportive phenotypes. In prostate cancer (search), the density of PD-L1+ tumor-associated nerves was found to be inversely correlated with CD8+ tumor-associated lymphocytes, suggesting these nerves contribute to an immunosuppressive microenvironment.
The central nervous system (CNS) exerts both local and systemic control over immunity. In glioblastoma (search) (GBM), neurons form glutamatergic synapses with glioma cells through calcium-permeable AMPA receptors, and blocking these receptors can hinder glioma growth. Neuronal activity-regulated paracrine factors, including neuroligin-3 (NLGN3) and brain-derived neurotrophic factor (BDNF), promote glioma progression by facilitating neuron-to-glioma synapse formation.
The enteric nervous system (ENS), often called the "second brain," influences cancer through the gut-brain-cancer axis. Gut microbiota metabolites, including short-chain fatty acids and tryptophan derivatives, modulate systemic processes affecting both brain health and tumorigenesis. In pancreatic ductal adenocarcinoma (search) (PDAC), intratumoral nerves serve as a rich source of neurotrophic factors and autonomic neurotransmitters that enhance cancer cell invasiveness and activate pro-survival signaling pathways.
Therapeutic Strategies in Translation
The most clinically advanced neuro-immune intervention involves beta-blockers. Propranolol, a non-selective β-adrenergic receptor antagonist, has shown promise in combination with immune checkpoint blockade (ICB). A retrospective evaluation of NSCLC patients treated with ICB found that those using β-blockers had higher survival rates than non-users. Similar results have been observed in metastatic melanoma, and Mellgard G et al. reported that β-blockers enhanced ICB clinical activity with significant association with overall survival in urothelial carcinoma.
A Phase I/II clinical trial (NCT03384836) is evaluating propranolol combined with pembrolizumab, with early data showing an increase in IFN-γ and a decrease in IL-6 in responders. Perioperative COX-2 and β-adrenergic blockade with propranolol has demonstrated improved immune biomarkers in breast cancer (search) patients in Phase II trials.
Preclinical strategies include surgical or pharmacological denervation, which has shown efficacy in gastric and prostate cancer (search) models. Multimodal neuro-nanotechnology, integrating nanotechnology-based delivery systems with neural regulation and immunotherapy, represents an emerging frontier for achieving spatiotemporally controlled modulation of the tumor microenvironment, though most applications remain preclinical.
Challenges and Future Directions
The review identifies several key challenges: the heterogeneity of neuro-immune interactions across cancer types, the bidirectional and dynamic nature of these interactions creating complex feedback loops, and the difficulty of translating preclinical findings given that human innervation patterns are difficult to fully recapitulate in animal models.
Future research directions include systematically mapping neuro-immune interactions across a broader spectrum of cancers using single-cell sequencing and spatial transcriptomics, developing highly specific and localized neuro-modulatory agents to minimize systemic toxicity, and deeper investigation of neuro-epigenetic regulation. The authors emphasize that epigenetic modifications—including DNA methylation, histone modifications, and non-coding RNA regulation—may represent a critical mechanistic layer through which neural signals reshape immune cell behavior in cancer, though direct evidence linking epigenetic regulation to neuroimmune interactions remains limited.
"Looking forward, integrating neuroscience, immunology, and oncology with emerging technologies may further elucidate the spatial and molecular architecture of neuroimmune interactions," the authors write, underscoring the potential for precision therapeutic targeting and tumor microenvironment reprogramming.