The tumor microenvironment (TME) is a dynamic and complex ecosystem composed of malignant cells, stromal elements, immune infiltrates, vasculature, and increasingly recognized neural components. These diverse cellular and molecular constituents engage in reciprocal interactions that shape tumor behavior, immune responses, and therapeutic outcomes. Within this evolving niche, nerve fibers and neuroactive signals integrate with immune and stromal pathways to modulate cancer progression, highlighting the TME as both a structural and signaling hub for tumor-neuron-immune crosstalk. Immune cells in the TME can be co-opted by tumors: for example, tumor associated macrophages and lymphocytes may secrete growth factors, remodel the extracellular matrix, and create immunosuppressive conditions which favors tumor growth and dissemination (de Visser and Joyce, 2023; Binnewies et al., 2018). Cancer-associated fibroblasts (CAFs) (Yang et al., 2023; Sahai et al., 2020), other stromal cells as well as the tumor cells produce extracellular matrix components and pro-tumorigenic signals that facilitate invasion and metastasis. Endothelial cells form blood vessels that provide nutrients for the growing tumors (Yao and Zeng, 2023; Akino et al., 2009). Immune suppressive myeloid cell populations such as the tumor associated macrophages (TAMs) or myeloid derived suppressor cells (MDSCs) suppress the anti-tumor immune responses (Cassetta and Pollard, 2023; Ouzounova et al., 2017; Bronte et al., 2016). Collectively, these interactions were conceptualized in the Hallmarks of Cancer, which include sustained proliferative signaling, resistance to cell death, angiogenesis, invasion, and metastasis (de Visser and Joyce, 2023; Hanahan, 2022) (Figure 1).

Norepinephrine released from sympathetic nerve terminals binds to β-AR (especially β₂) on tumor cells, activating cAMP/PKA and downstream pathways (AKT, NF-κB, STAT3) that drive tumor proliferation, angiogenesis, invasion, and metastasis (Wang et al., 2025). This adrenergic signaling strongly promotes tumorigenesis via upregulating VEGF and MMPs, facilitating angiogenesis and matrix remodeling, while also inhibiting apoptosis, thereby giving cancer cells a growth and survival advantage (Qi et al., 2022).

Acetylcholine from parasympathetic neurons binds muscarinic acetylcholine receptors on tumor cells. This triggers pro-invasive and pro-proliferative signals (via PI3K/AKT, MEK/ERK, and NF-κB pathways), leading to increased production of matrix metalloproteinases and other factors that enhance tumor cell motility and invasiveness (Zhang et al., 2025b). In some cancers, cholinergic signaling can also influence epithelial-mesenchymal transition (EMT) and metastatic dissemination (Fu et al., 2024; Zhao et al., 2015). Notebly, the impact of parasympathetic signaling appears contecxt-dependent. While it promotes invasion in gastric and colon cancer, it may also exert protective or suppressive effects in other malignancies. In prostate cancer, parasympathetic signaling has been linked to promoting later stages of tumor dissemination (Wang et al., 2021). These divergent roles underscore the need for tumor-type-specific analyses of cholinergic pathways.

Substance P released by sensory nerve fibers binds to neurokinin-1 receptors (NK-1R) on cancer cells. Activation of NK-1R by SP potently promotes tumor cell proliferation and migration, stimulates angiogenesis, enhances cancer cell metabolism, and inhibits apoptosis in number of solid tumors (Ebrahimi et al., 2020; Chen et al., 2016; Huang et al., 2018). This SP/NK-1R signaling axis contributes to aggressive tumor behavior; for example, in pancreatic cancer, substance P–NK-1R signaling drives perineural invasion of cancer cells into nerves, a process associated with pain and metastasis (Zhang et al., 2025b; Ye et al., 2023). Tumor cells often overexpress NK-1R to exploit these pro-tumor effects of SP, and blocking SP-NK1R has been shown to suppress tumor growth (Chen et al., 2016; Zhang et al., 2025b; Munoz et al., 2020; Munoz and Covenas, 2020).

Sympathetic nerves co-release neuropeptide Y (NPY), which can act on its receptors in the tumor microenvironment. NPY signaling is strongly linked to cancer progression, influencing tumor growth, migration, invasion, and blood vessel formation (Pascetta et al., 2023; Zhang et al., 2025b). For instance, upregulation of NPY Y1 and Y5 receptors in breast tumors correlates with greater cancer cell proliferation and migration (Pascetta et al., 2023). NPY/Y receptor axis also promotes angiogenesis in breast cancer by inducing VEGF (Medeiros and Jackson, 2013), cell survival and motility via activation of p44/42-MAPK pathway and RhoA signaling respectively in neuroblastoma (Abualsaud et al., 2020; Czarnecka et al., 2015).

Norepinephrine (and epinephrine) signaling through β-adrenergic receptors on tumor cells leads to increased expression of PD-L1 on the cancer cell surface and blockade of β₂-adrenergic receptors reduces cancer growth and enhances response to anti-CTLA4 therapy (Wang et al., 2025; Fjaestad et al., 2022). Elevated PD-L1 allows tumor cells to engage PD-1 receptors on T cells, turning off T cell responses and thereby enabling the tumor to escape cytotoxic T cell attack. NE-driven β-AR activation has been shown to directly suppress T cell activity in this manner, contributing to immune evasion (Wang et al., 2025; Nissen et al., 2018).

Neural inputs also influence macrophage polarization in the tumor microenvironment. Tumor associated macrophages can be skewed toward M2 (immunosuppressive) phenotype by neural factors (Wang et al., 2025). For example, substance P released by sensory nerves binds neurokinin-1 receptors (NK-1R) on macrophages, inducing M2 polarization (Lim et al., 2017). These M2 TAMs secrete anti-inflammatory cytokines (e.g., TGF-b, IL-4 and IL-10) and growth factors, while inhibiting Th1-type immune responses, thereby suppressing T cell and NK cell anti-tumor activity. Similarly, stress-induced norepinephrine (NE) activates β-adrenergic receptors on macrophages, driving M2-like gene expression programs in breast cancer (Qin et al., 2015b). In addition, neural signals may modulate dendritic cell differentiation and antigen presentation capacity, further compounding immune evasion.

Chronic activation of the sympathetic nervous (SNS) system negatively impacts adaptive and innate immune effector cells. T lymphocytes exposed to elevated NE levels exhibit reduced cytokine production (e.g., IFN-g), impaired proliferation, and increased expression of exhaustion markers such as PD-1, TIM-3 and LAG-3. v (Mohammadpour et al., 2019; Nissen et al., 2018). β2-adrenergic receptor activation on CD8⁺ T cells suppresses their cytolytic function and hampers memory formation. In line with this notion, NK cells experience functional inhibition through NE-mediated suppression of perforin and granzyme B release, mediated by cAMP/PKA signaling (Zhang et al., 2025a; Sun et al., 2018). These immunosuppressive effects culminate in decreased immune infiltration and impaired tumor clearance.

The neuron-modulated immunosuppressive tumor microenvironment contributes to resistance against wide range of anti-cancer therapies. Catecholamines released during chronic stress inhibit immune-mediated tumor destruction and foster a TME dominated by suppressive myeloid cells. Tumors in high catecholamine contexts exhibit poor response to immune checkpoint blockade (ICB), chemotherapy, and radiotherapy (Zhang et al., 2025a; Mohammadpour et al., 2019; Inigo-Marco and Alonso, 2019). For instance, β-adrenergic signaling enhances DNA damage repair in tumor cells and upregulates PD-L1 expression, diminishing T-cell–mediated cytotoxicity (Inigo-Marco and Alonso, 2019; Nissen et al., 2018; Farooq et al., 2023; Oh et al., 2021). Studies have demonstrated that β-blockade reverses these effects: β-blockers reduce MDSC infiltration, restore T and NK cell function, and sensitize tumors to ICB. In NSCLC patients, concurrent use of β-blockers with ICB has been associated with prolonged progression-free survival, suggesting translational relevance (Oh et al., 2021). By blocking the stress pathways, T cells and NK cells can regain function, leading to improved anti-tumor immunity.

This reciprocal relationship adds a new layer to the tumor microenvironment’s complexity, sometimes described as the “neural niche” of the tumor (Termini et al., 2014). Importantly, neural involvement is not a rare occurrence; nerves are present in many solid tumors, and their density often correlates with more advanced disease or worse patient outcomes (Wang et al., 2021; Wang et al., 2024b).

The concept of a “neural niche” captures this reciprocal relationship between cancer and nerves, whereby neuronal activity drives immune suppression and tumor plasticity. This niche integrates neurotrophic factors, neurotransmitters, and immune regulators into a coordinated network that sustains tumor progression. Clinical evidence supports the oncogenic role of neural innervation: elevated intratumoral nerve density correlates with worse prognosis in cancers such as colon, rectal, breast, and head and neck carcinomas (Silverman et al., 2021). Intriguingly, spinal cord injury patients, who lose autonomic innervation to specific organs, show a markedly reduced risk of developing prostate cancer (Rutledge et al., 2017), emphasizing the dependence of some tumors on neural support.

The nervous system’s role in cancer progression spans from tumor initiation to metastasis. Neuronal signals can create a microenvironment conducive to transformation of cells with oncogenic mutations (Tibensky and Mravec, 2021). For example, in pre-malignant lesions of the pancreas and prostate, increased nerve fiber density has been observed, suggesting that neurogenesis and axonogenesis may be early events that support tumor development (Wang et al., 2021; Li et al., 2022). Growing tumors are often become richly innervated (Baraldi et al., 2022). Research has demonstrated that nerves actively infiltrate tumors in multiple cancer types (pancreatic, colorectal, prostate, breast, head and neck, among others) and that this innervation fuels tumor growth and metastasis (Wang et al., 2021; Zhang et al., 2025a; Li et al., 2022). Tumor-associated nerves with an increased neural activity facilitate tumor growth and metastasis by releasing growth-promoting molecules.

The bidirectional cancer-nerve communication allows them exchange signals which drives an increased neurogenesis of nerves while inducing aggressive properties of the tumor cells (Zhang et al., 2025a; Wen et al., 2025; Wu et al., 2023). Tumor cells “hijack” the nervous system by releasing neurotransmitters, neurotrophic factors, and axon guidance molecules that stimulate nerve growth or reprogram nearby neurons (Wang et al., 2021; Zhang et al., 2025a; Yang et al., 2024; Wang et al., 2024b; Li et al., 2022). One striking example is in prostate cancer: tumors can induce a switch in adjacent neurons, causing typically sensory nerves to acquire adrenergic (sympathetic) features that promote tumor progression (Wang et al., 2021; Ferdoushi et al., 2021; Cervantes-Villagrana et al., 2020). This phenomenon of neuronal reprogramming illustrates how cancer can manipulate nerve biology to its advantage, effectively creating a positive feedback loop. In line with this notion, head and neck cancers with loss of p53 was able to reprogram infiltrating neurons (Amit et al., 2020). Another example is in breast cancer brain metastases, where cancer cells have been found to co-opt neuronal synapses, they engage with glutamatergic synaptic inputs from brain neurons to receive growth signals via NMDA-type glutamate receptors (Neman et al., 2014). This direct synaptic interaction helps seeded cancer cells generate metastasis in the brain microenvironment.

Clinical and experimental denervation studies further validate the functional significance of nerves in cancer (Li et al., 2022; Espana-Ferrufino et al., 2018; Lei et al., 2017; Jiang et al., 2014; Deng et al., 2014b; Bapat et al., 2011). Surgical or chemical ablation of nerves in murine models reduces tumor growth and metastasis (Boilly et al., 2017). Patients with diminished autonomic tone such as vagotomy or nerve injury exhibit reduced cancer risk or improved survival in some context (Patel et al., 2011). Conversely, higher intra-tumoral nerve density in colon and rectal cancer patients has been associated with advanced stage and poorer survival (Albo et al., 2011). Together, these findings support the idea that many cancers are, to some degree, nerve-dependent, they rely on neural support or stimulation, a concept sometimes termed the “neural addiction” of cancer (Magnon and Hondermarck, 2023).

Neural regulation also intersects with cancer stemness and immune modulation. In triple-negative breast cancer, stemness-associated non-coding RNAs (lncRNA) correlate with distinct immune landscape and ICB responsiveness (Wu et al., 2023). These data imply that neurotrophin- and neurotransmitter-driven signaling in the TME may intersect with lncRNA-mediated stemness circuits to promote immune evasion, therapy resistance and clinical outcome (Feng et al., 2021). Integrating neurotrophic signaling, stemness, and immune biomarkers could therefore refine risk stratification and guide personalized therapeutic strategies.

Emerging evidence supports the role of neuroendocrine stress responses as a critical systemic regulator of cancer progression, bridging central nervus system stress circuits with peripheral immune modulation. The hypothalamic-pituitary-adrenal (HPA) and sympathetic-adrenal-medullary (SAM) axes orchestrate this crosstalk, functioning as systemic extension of the tumor neural niche. Under chronic psychosocial stress or tumor-induced stress, elevated levels of cortisol and catecholamines reshape the tumor microenvironment and immune landscape tipping the balance toward tumor tolerance and therapy resistance.

This integration expands the understanding of tumor-nerve-immune crosstalk beyond local innervation to include brain-periphery signaling loops. Notably, the effects of chronic stress and systemic catecholamine/glucocorticoid signaling appear to be context-dependent, with tumor-type, disease stage and local immune landscape shaping the magnitude and directionality of the neuroendocrine influence. The hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary (SAM) axis, the body’s principal neuroendocrine stress systems, play key roles in modulating tumor biology (Vignjevic Petrinovic et al., 2023). Chronic activation of these axes (as seen in prolonged psychosocial stress or tumor-induced stress) leads to elevated glucocorticoids (cortisol) and catecholamines (epinephrine/norepinephrine), which can reshape the tumor microenvironment and immune surveillance (Khan et al., 2025). For example, persistent HPA/SAM activation can suppress antitumor immunity and promote a tumor-favorable milieu: stress-elevated catecholamines reduce the infiltration and efficacy of cytotoxic immune cells, inhibit cancer cell apoptosis, and induce epithelial-mesenchymal transition (EMT) and angiogenesis, collectively accelerating tumor growth, invasion and metastasis (Slominski et al., 2023). Glucocorticoids released from adrenal and extra-adrenal sources via HPA activation likewise exert immunosuppressive effects, dampening anti-tumor immune responses and skewing the balance toward tumor tolerance (Swatler et al., 2023; Slominski et al., 2024; Slominski et al., 2020). Importantly, these neuroendocrine stress signals have been linked to therapy resistance as tumors under chronic stress often exhibit poorer responses to chemotherapy and immunotherapy (Zhang et al., 2022a). Adrenergic signaling can upregulate survival pathways in cancer cells and impede immune-mediated tumor clearance, reducing treatment efficacy (Nissen et al., 2018; Zhang et al., 2024). Systemically, β-adrenergic signaling has been shown to suppress dendritic cell maturation, reduce antigen-presentation capacity and enhance regulatory (Treg) expansion, all contributing to a tolerogenic immune landscape that protects tumor from immune attack (Mohammadpour et al., 2019). Conversely, emerging studies suggest that blocking stress pathways can improve therapeutic outcomes: pharmacological inhibition of β-adrenergic receptors (β-blockers) or other adrenergic modulators can restore anti-tumor immune activity and has shown potential to enhance the efficacy of chemotherapy, immunotherapy, and targeted therapies (Fjaestad et al., 2022; Slominski et al., 2025). These findings underscore the clinical significance of neuroendocrine stress circuits and managing patient stress or pharmacologically modulating HPA/SAM activity may limit tumor progression and overcome therapy resistance.

While most mechanistic insights are driven from murine models, emerging retrospective clinical studies are beginning to validate the translational potential of neuroendocrine modulation in improving immunotherapy responsiveness and overall survival, particularly in cancers such as melanoma, NSCLC and breast cancer.

HPA and SAM axis form a coordinated neuroendocrine interface between the brain, immune system, and peripheral tissues that tumors can exploit. Activation of the SAM axis (sympathetic nervous system and adrenal medulla) during stress leads to surges of epinephrine and norepinephrine, which bind β-adrenergic receptors on both tumor cells and various immune cells. This adrenergic stimulation has pleiotropic pro-tumor effects: it can directly stimulate cancer cell proliferation, survival, migration, and angiogenesis, and indirectly suppress anti-tumor immune functions (Zhang et al., 2024). For instance, β-adrenergic signaling skews immune cell differentiation and cytokine secretion toward an immunosuppressive profile, impairs the cytotoxicity of natural killer (NK) cells and T lymphocytes, and promotes the accumulation of pro-tumoral macrophages (Mohammadpour et al., 2019; Fjaestad et al., 2022). At the same time, stress-induced HPA activation elevates systemic cortisol, which further inhibits immune surveillance by inducing T cell apoptosis and impairing antigen presentation (Chen et al., 2022). Through these mechanisms, heightened activity of the HPA/SAM axes under chronic stress conditions creates an “immunosuppressive shield” around the tumor, allowing cancer cells to evade immune destruction and facilitating malignant progression (Chen et al., 2022; Zheng et al., 2025). In line with this, clinical and preclinical studies have observed that sustained psychosocial stress or depression (which often involves HPA axis dysregulation and hypercortisolism) is associated with faster tumor growth and metastasis in various cancers (Huang et al., 2025). Conversely, parasympathetic/vagal signaling, which often counterbalances sympathetic activity, may exert tumor-inhibitory effects in some contexts. For example, subdiaphragmatic vagotomy led to increased tumor growth and reduced survival in syngeneic models of murine pancreatic cancer (Renz et al., 2018a; Parteck et al., 2017). These observations highlight that the balance of autonomic tone influences cancer outcomes: sympathetic stress pathways generally promote tumor progression, whereas restoring parasympathetic activity or reducing adrenergic drive may improve anti-tumor immunity.

Stress-mediated immunosuppression and pro-survival signaling in tumors contribute to resistance against therapies. For instance, elevated catecholamine levels have been linked to reduced efficacy of immune checkpoint blockade and chemotherapy, partly by impairing T cell function and enhancing DNA damage repair in tumor cells (Zhang et al., 2024). On the other hand, disrupting these neuroendocrine signals can render tumors more vulnerable to treatment. Preclinical research and epidemiological data suggest that patients on β-blockers (adrenergic antagonists) sometimes show improved outcomes in certain cancers, presumably by abrogating adrenergic support of tumor growth and metastasis (Sharma et al., 2025). As noted above, pharmacological modulation of stress circuits, such as using β-adrenergic or α-adrenergic receptor blockers, is being explored to enhance the efficacy of chemotherapy, immunotherapy, and targeted therapy in cancer patients (Carnet Le Provost et al., 2023; Kokolus et al., 2018). Additionally, behavioral or psychosocial interventions that reduce chronic stress (exercise, meditation, counseling) could theoretically dampen HPA/SAM overactivity and thereby bolster the patient’s endogenous anti-tumor immunity. Together, these insights into the HPA and SAM axes underscore a paradigm in which cancer is not only a disease of genetic mutations but also a systemic maladaptation of stress-immune homeostasis.

Catecholamines released by sympathetic nerves can bind β₂-adrenergic receptors on myeloid cells, notably on myeloid derived suppressor cells (MDSCs) (Mohammadpour et al., 2019; Mohammadpour et al., 2021). Chronic adrenergic stimulation significantly increases MDSC recruitment, survival, and immunosuppressive function in tumors (Mohammadpour et al., 2019; Farooq et al., 2023). Under β-AR signaling, MDSCs upregulate enzymes like arginase-I and inhibitory ligands like PD-L1, and more effectively suppress T cell proliferation (Mohammadpour et al., 2019; Schuster et al., 2023). β-Adrenergic agonists were also shown to activate inflammatory signaling via TLR2 which may play role in MDSC induction and expansion (Agac et al., 2018; Manni et al., 2011). These stress-expanded MDSCs produce IL-10, TGF-β and other factors that inhibit effector lymphocytes and even impair NK cell function (Mohammadpour et al., 2019; Inigo-Marco and Alonso, 2019). Collectively, expansion of immune suppressive myeloid cells and diminished cytotoxic lymphocytes will lead to an immunosuppressive microenvironment dominated by MDSCs and M2-polarized macrophages.

PNI occurs when cancer cells actively invade the spaces surrounding nerves, often migrating along the nerve sheath. Histopathologically, PNI is typically defined by the presence of tumor cells within the perineural space or encircling the nerve sheath (Chavan et al., 2017). PNI can be further subclassified into purely perineural (tumor outside but circumferentially surrounding the nerve) and intraneural (tumor breaching the perineurium and infiltrating within the fascicles), with the latter often reflecting more advanced disease (Chen et al., 2019; Wang et al., 2024b; Liang et al., 2016). Grading schemes commonly distinguish: Grade 0 (no PNI), Grade 1 (perineural involvement without intraneural spread), and Grade 2 (overt intraneural invasion with distortion of nerve architecture).

PNI is a common feature in many malignancies, notably pancreatic, head and neck, prostate, and colorectal cancers, and is strongly associated with metastasis, recurrence, and pain (Huang et al., 2025). Tumor cells that disseminate via nerves can travel to distant sites by tracking along nerve bundles which is distinct from circulation in lymphatics or bloodstream, and it often correlates with especially aggressive disease. Clinically, the detection of PNI in a tumor biopsy is considered an adverse prognostic indicator for number of solid tumors (Nozzoli et al., 2024; Narayan et al., 2021). For example, in pancreatic ductal adenocarcinoma, PNI is extremely prevalent and contributes to severe pain experienced by patients, as well as it is associated with earlier local recurrence after surgery (Liang et al., 2016).

Cancer cells in PNI exhibit invasive behavior which is driven by signals from the nerves and Schwann cells that foster a permissive niche. Indeed, recent work shows that PNI formation is orchestrated by an array of molecular and cellular interactions: neurotrophins, chemokines, and cytokines provide chemical cues, while Schwann cells and immune cells (like macrophages and T cells) actively participate in enabling cancer cells to infiltrate nerves (de Visser and Joyce, 2023; Zhang et al., 2025a). This multifactorial coordination not only facilitates tumor spread along nerves but also leads to neuropathic cancer pain, as nerve integrity is compromised.

Tumor innervation refers to the growth of new nerves into the tumor tissue via the tumor cell secreted factors which attract neuronal axons inducing nerve sprouting within the tumor (Payton, 2013). This result in increased nerve fiber density within the tumor. This kind of neo-innervation has been reported in number of solid tumors including prostate cancer, breast cancer and gastric cancer (Wang et al., 2021; Wu et al., 2023; Nozzoli et al., 2024). For instance, prostate tumors in mouse models have been shown to stimulate dense sympathetic and parasympathetic nerve ingrowth, which in turn enhances tumor progression and dissemination (Silverman et al., 2021; Magnon et al., 2013). Mechanistically, tumor-produced growth factors serve as chemoattractants for neurites. Histological examination of tumors often reveal nerve fascicles penetrating into the tumor stroma; these nerves may form synapse-like structures with cancer cells or release neurotransmitters locally (Nguyen et al., 2023). Tumor innervation often accompanies PNI in a vicious cycle, as tumor cells invade nerves, they can also prompt further nerve growth, generating a tumor-nerve network. Both PNI and active innervation are indicators of a high degree of tumor-nerve interplay, and both are linked to more aggressive tumor phenotypes (Gysler and Drapkin, 2021). Advent of advanced spatial imaging and tracing technologies facilitated the deeper characterization of these tumor-nerve networks demonstrating that some tumors establish long-distance connections with the nervous system. For example, nerves from ganglia or the spinal cord may extend processes into a tumor, potentially allowing central neural influences to directly impinge on tumor cells (Wang et al., 2021; Reavis et al., 2020).

Extensive studies collectively suggest that PNI and tumor innervation are two sides of the cancer-neuron interaction. PNI reflects tumor cells moving into neural territory, whereas innervation reflects nerves growing into the tumor territory. Both phenomena often coexist and reinforce one another. Clinically, their presence underscores the need to consider nerves as both diagnostic markers and potential therapeutic targets in cancer management.

Beyond local neural remodeling, neurogenic signals can influence systemic dissemination by modulating circulating tumor cells (CTCs). CTCs constitute a critical intermediate between primary tumors and distant metastases and are now monitored using a variety of in vivo and in vitro detection platforms that also inform immunotherapy response (Zhan et al., 2023). Stress-related adrenergic signaling and neurotrophin-rich microenvironments may enhance CTC survival, epithelial–mesenchymal plasticity and immune escape, thereby linking the neural niche to the systemic tumor–immune interface (Triaca et al., 2019). Although the studies are limited on this area, incorporating CTC metrics into cancer-neuron-immune crosstalk will be essential to fully understand and therapeutically target the metastatic cascade.

Dopamine receptors are expressed on tumor and immune cells in several solid tumors. Depending on receptor subtype and context, dopamine can inhibit angiogenesis and tumor growth via D2 receptor-mediated suppression of VEGF signaling or support tumor-promoting inflammation through D1-coupled pathways (Peters et al., 2020; Sobczuk et al., 2020). On immune cells, dopamine modulates T cell activation and NK cell cytotoxicity, indicating that dopaminergic signaling can drive anti-tumor immunity (Chovar-Vera et al., 2022). In contrast, elevated D2 dopamine receptor (DRD2) is shown to drive tumor progression via hypoxia-inducible factor-1α (HIF-1α) in mouse melanoma tumor model (Liu et al., 2021).

Serotonin functions as a growth and motility factor in multiple epithelial cancers through 5-HT receptors and downstream ERK/AKT signaling (Karmakar and Lal, 2021; Peters et al., 2020). It also shapes the tumor immune microenvironment by regulating myeloid cell recruitment, T cell function and cytokine production; attenuation of peripheral serotonin inhibits tumor growth and improves responses to immune checkpoint blockade in preclinical models (Schneider et al., 2021; Karmakar and Lal, 2021).

Glutamatergic neurotransmission is particularly relevant in primary brain tumors and brain metastases. Gliomas and metastatic breast cancer cells can release and respond to glutamate, engaging AMPA and NMDA receptors to drive proliferation, invasion and synapse-like contacts with neurons (Zeng et al., 2019; Sontheimer, 2008). These neuro-cancer synapses support electrical and metabolic coupling that enhances malignant growth and may confer resistance to therapy.

Neuropeptides such as substance P, calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) are released by sensory and autonomic fibers and act on GPCRs expressed by tumor, endothelial and immune cells (Sun et al., 2024; Shalabi et al., 2024). Substance P–NK1 signaling promotes cancer cell migration, angiogenesis and mast cell activation; CGRP and VIP can suppress anti-tumor immune responses by inhibiting dendritic cell maturation and T cell activation. Targeting neuropeptide–receptor axes therefore represents another opportunity to modulate both tumor and immune compartments of the neural niche.

Tumors innervation may indeed release a cocktail of neurotransmitters into the TME, while tumor cells also produce or respond to these neurotransmitters. The outcome is a neurochemical dialogue that can significantly skew tumor biology and the clinical outcome for the patients. Blocking specific neurotransmitter receptors on tumor cells (for example, using β-adrenergic blockers, or muscarinic receptor antagonists) has emerged as a potential strategy to disrupt the pro-tumor effects of nerves. Moreover, stress reduction and β-blockade have been investigated clinically to see if they can improve cancer outcomes by dampening adrenergic signaling.

In prostate cancer models, surgical sympathectomy reduces early tumor incidence, while pelvic parasympathetic denervation diminishes distant metastasis, indicating stage-specific roles for autonomic inputs (Magnon et al., 2013). Vagotomy or local botulinum toxin–mediated cholinergic blockade suppresses gastric tumorigenesis and prolongs survival, supporting a critical role of cholinergic signaling in gastric cancer progression (Rabben et al., 2021; Zhao et al., 2014). In pancreatic cancer, experimental vagotomy accelerates tumor growth whereas sympathetic ablation reduces cancer stemness and tumor burden, highlighting the importance of autonomic balance rather than unidirectional effects (Renz et al., 2018a; Parteck et al., 2017; Saloman et al., 2016).

Chemical sympathectomy with 6-hydroxydopamine (6-OHDA) depletes norepinephrine-containing fibers and reduces stress-induced tumor growth and metastasis in breast and ovarian cancer models (Zhang et al., 2024; Conceicao et al., 2021; Szpun et al., 2016). TRPV1-targeted approaches or capsaicin-based sensory denervation blunt neurogenic inflammation and attenuate nerve-facilitated invasion in pancreatic and colorectal cancer (Zhang et al., 2025c; Schwartz et al., 2011).

Genetic disruption of neural growth or signaling further supports a causal role of nerves. Deletion or pharmacological inhibition of RET or Trk family receptors (TrkA/B) impairs GDNF- and NGF-driven axonogenesis toward tumors and reduces perineural invasion in pancreatic and head and neck cancer models (Lin et al., 2020; Hua et al., 2016; Thiele et al., 2009). Tumor or host-specific β₂-adrenergic receptor (Adrb2) deletion protects against chronic stress-enhanced tumor growth and reverses β-adrenergic gene signatures associated with metastasis (Renz et al., 2018b; Al Khashali et al., 2023). Knockdown of NGF or its receptors in gastric and prostate cancer models decreases tumor nerve density, neuroendocrine differentiation, and PNI, further illustrating a feed-forward neurotrophic loop (40,61,73). Furthermore, adrenergic nerve-derived noradrenaline in the prostate cancer stroma was shown to activate an angiogenic switch fueling tumor growth via alteration of endothelial cell metabolism (Zahalka et al., 2017). Deletion of endothelial Adrb2 gene inhibited angiogenesis in the tumor stroma and reduced prostate cancer progression.

A growing body of evidence demonstrates that β-adrenergic signaling regulates both tumor cell and the microenvironment, integrating neural inputs into cancer progression. Across multiple cancer types, chronic activation of β-adrenergic receptors (β-ARs) not only enhances tumor cell intrinsic programs but also profoundly reshapes antitumor immunity. Mechanistically, β-AR stimulation directly impairs cytotoxic CD8⁺ T cell expansion, IFNγ production, and killing capacity, thereby diminishing responsiveness to immunotherapies (Zhang et al., 2024; Carnet Le Provost et al., 2023). At the tumor cell level, β-adrenergic agonists increase traction forces, stiffness, and invasive potential in triple-negative breast cancer cells through a βAR–RhoA–ROCK–myosin II axis, demonstrating that stress-related catecholamines mechanically prime cancer cells for metastasis (Kim et al., 2025). Conversely, β-blockade with propranolol reveals the extent to which this neural signaling suppresses antitumor immunity: inhibiting β-ARs drives a potent Th1-polarized cytotoxic CD4⁺ T cell response, reduces monocyte-mediated immunosuppression, and significantly attenuates metastasis in multiple tumor models while synergizing with CTLA-4 blockade (Fjaestad et al., 2025). Pharmacological blockade of β-adrenergic receptors with non-selective (propranolol) or selective (atenolol, metoprolol) β-blockers mitigates tumor growth, angiogenesis, invasion, and recruitment of tumor-promoting macrophages across several models (Fjaestad et al., 2022; Carnet Le Provost et al., 2023). Combining β-blockers with immune checkpoint inhibitors enhances anti-tumor T cell function and reduces exhaustion markers (Fjaestad et al., 2022; Globig et al., 2023), indicating that neural targeting can reprogram the immune landscape. Together, these studies position β-adrenergic signaling as a central node linking neural activity to tumor progression, mechanical adaptation, and immune evasion, implicating adrenergic blockade as a promising therapeutic strategy to disrupt neuro-immune circuits.

Collectively, these denervation, β-blockade, and gene-knockout models demonstrate that autonomic and sensory nerves are functionally required for full malignant progression in many solid tumors, supporting the concept of “neural addiction” in cancer (Boilly et al., 2017; Magnon and Hondermarck, 2023).

Tumors are innervated by multiple nerve types (sympathetic, parasympathetic, sensory), but their relative contributions can vary by cancer type and stage. For instance, sympathetic adrenergic signaling often promotes early tumor growth and angiogenesis, whereas parasympathetic (cholinergic) signals have been reported to either facilitate late-stage metastasis or, conversely, to inhibit tumor progression in certain contexts (Renz et al., 2018a). The controversy remains unresolved on parasympathetic signals restraining tumors instead of fueling them. In our view, the field must disentangle the context-dependent roles of different neural circuits, including sensory nerve-released neuropeptides such as SP and CGRP in various tumor microenvironments. It is still unclear which neural inputs are most critical at distinct tumor phases (initiation, progression, metastasis, or dormancy) and how they dynamically interact. Addressing this requires longitudinal and tissue-specific studies, as well as tools to selectively manipulate one neural subtype at a time.

Neuroimmune crosstalk within tumors is undeniably complex. While there is consensus that chronic sympathetic signaling creates an immunosuppressive TME (via TAM polarization, MDSC expansion, T cell dysfunction (Sattler et al., 2025) some findings suggest nuanced or even opposing effects under different conditions. For example, β-adrenergic signaling can sometimes enhance certain immune functions (e.g., mobilization of immune progenitors or neutrophils) at lower concentrations, yet potently suppress anti-tumor immunity when stress-related NE levels are high (Qin et al., 2015b). This dose- and context-dependent immune modulation is not fully understood. Similarly, dopamine and serotonin have immunomodulatory roles that can tilt toward immune activation or suppression based on receptor subtypes engaged. Open questions: How do neural signals integrate with checkpoint pathways and cytokine networks in the TME? Might there be situations where neural inputs actually enhance immune surveillance (for instance, transient sympathetic activation boosting antigen presentation) rather than suppress it? Advanced in vivo imaging and single-cell sequencing of innervated tumors may help map these interactions with high resolution.

Most research to date has examined local interactions (nerves within the tumor). However, tumors exist in a whole-body context where the central nervous system (CNS) and endocrine systems respond to malignancy. Psychosocial stress, for example, elevates systemic sympathetic output and cortisol levels (via the HPA axis), which can accelerate tumor progression in animal models (Wang et al., 2025). Yet we lack a clear picture of how brain-mediated factors (stress, circadian rhythms, neurological co-morbidities) influence tumor-immune interactions. Do central neural circuits (like hypothalamic or brainstem pathways) actively “sense” tumors and modulate peripheral immunity accordingly? Conversely, to what extent can tumors send afferent neural signals to the brain to induce behavioral changes (pain, depression, cachexia) that loop back and affect tumor growth (Zhu et al., 2025). These brain-body feedback loops represent a Frontier of cancer neuroscience (Zhu et al., 2025). Unraveling them will require interdisciplinary approaches, integrating neuroimaging, neural circuit manipulation (e.g., vagus nerve stimulation or beta-blockade), and monitoring of systemic physiological changes in cancer patients.

Another major hurdle in the field is the lack of experimental models that fully recapitulate human tumor-nerve-immune circuitry. Standard cell culture systems lack innervation and immune components. Co-culture models using neurons (e.g., dorsal root ganglia co-cultured with tumor organoids) provide valuable insights (Joseph et al., 2025) but still cannot mimic systemic influences (like brain inputs or endocrine signals). In vivo murine models have demonstrated the importance of innervation (e.g., surgical or pharmacologic denervation often slows tumor growth (Magnon et al., 2013), yet these models often use young mice without comorbidities or chronic stress, potentially underrepresenting the neuroimmune complexity seen in patients. Moreover, species differences (mouse neurons vs. human) and the short timescale of murine experiments may not capture the chronic neural remodeling of human cancers.