Sensory-nerve involvement in gastric cancer is a critical yet understudied facet of tumor neurobiology, with dual roles in pain pathogenesis and modulation of the tumor microenvironment [27]. Sensory fibers arising from the dorsal root and trigeminal ganglia densely innervate the gastric mucosa and submucosa, and they undergo marked remodeling during carcinogenesis [28]. In gastric cancer, these fibers show altered distribution patterns, with increased density at the tumor periphery and selective depletion in necrotic tumor cores, suggesting dynamic interactions between growing malignancies and sensory innervation [29]. This spatial reorganization correlates with clinical pain manifestations, as tumor-associated neural sprouting and sensitization contribute to the characteristic visceral pain in advanced disease. The pain mechanisms involve both direct tumor compression of nerve bundles and molecular crosstalk through neuroactive substances released by cancer cells, such as ATP, protons, and growth factors, which activate sensory neurons through specific receptors (TRPV1, ASICs, and P2X3) [30].

SP and CGRP, the principal neuropeptides released by sensory nerves, serve as key mediators in the neuro-tumor dialogue. SP, acting via the neurokinin-1 receptor (NK1R), exerts multifaceted protumor effects in gastric cancer. NK1R-positive tumor cells respond to SP with increased proliferation and migration through mitogen-activated protein kinase/extracellular signal–regulated kinase (MAPK/ERK) pathway and NF-κB activation [31]. Within the vascular compartment, SP promotes angiogenesis by upregulating vascular endothelial growth factor (VEGF)in both cancer cells and tumor-associated macrophages and concurrently increases vascular permeability, thereby facilitating metastatic dissemination. SP also amplifies inflammation by inducing interleukin-6 (IL-6) and interleukin-8 (IL-8) secretion from stromal cells, generating a pro-tumorigenic cytokine milieu. Clinically, elevated SP levels in gastric cancer tissue correlate with advanced disease stage and poorer prognosis, suggesting its potential as both a therapeutic target and prognostic biomarker [32].

CGRP, a pivotal sensory neuropeptide, exerts context-dependent effects in gastric cancer. By binding to calcitonin receptor-like receptor/receptor activity-modifying protein (CLR/RAMP) complexes, CGRP modulates tumor-associated inflammation by skewing macrophage polarization towards an M2-like, pro-tumor phenotype. Its vasodilatory activity contributes to the aberrant vascular architecture typical of gastric tumors, and emerging data indicate direct mitogenic effects on cancer stem-like cells [33]. Paradoxically, CGRP may also exert anti-inflammatory effects in some contexts, highlighting the complexity of sensory neuropeptide signaling in cancer [34]. Both SP and CGRP promote pain via peripheral and central sensitization, lowering nociceptive thresholds and amplifying spinal pain transmission. The therapeutic implications of targeting sensory nerve-tumor interactions are increasingly evident. NK1R antagonists, originally developed as antiemetics, have shown preclinical efficacy in reducing gastric cancer growth and metastasis while alleviating cancer pain. Similarly, CGRP receptor antagonists, currently used for migraine treatment, may find application in managing gastric cancer-associated pain and potentially modifying tumor progression. Emerging approaches that combine neuromodulation with conventional treatments aim to simultaneously control tumor progression and cancer pain, offering a promising multidisciplinary strategy. Nevertheless, precise targeting of these pathways remains challenging, as interventions must avoid disrupting normal pain perception and sensory function [35].

Current research highlights the bidirectional nature of sensory nerve–tumor interactions: cancer cells not only respond to neuropeptides but also recruit and reprogram sensory nerves via nerve growth factor (NGF) and other neurotrophic factors, establishing a self-reinforcing cycle that drives tumor progression and pain chronification. Single-cell RNA sequencing studies are beginning to reveal the heterogeneity of sensory neuron subpopulations infiltrating gastric tumors, opening new possibilities for selective therapeutic intervention [36]. Furthermore, the intersection between sensory signaling and immune checkpoint regulation presents intriguing opportunities for combination therapies that might enhance the efficacy of existing immunotherapies while providing analgesia [37].

Defining the precise spatiotemporal dynamics of sensory-nerve involvement remains a central challenge. Advanced imaging techniques and neural tracing methods are being employed to map the anatomical and functional reorganization of sensory innervation during tumor progression [38]. These investigations may identify critical windows for therapeutic intervention and help develop biomarkers for predicting pain risk and progression patterns. As cancer neuroscience advances, targeting sensory nerve–tumor interactions could emerge as a fourth pillar of gastric-cancer therapy, complementing surgery, chemotherapy, and radiation [39] (Table 1).

Recent advances in cancer neuroscience have revealed the existence of functional synaptic connections between neurons and cancer cells, termed “neuro-tumor synapses.” These specialized structures facilitate direct electrochemical communication through neurotransmitter release and receptor activation. In gastric cancer, such synapses predominantly involve glutamatergic and adrenergic signaling, where presynaptic neurons release neurotransmitters that bind to corresponding receptors on cancer cells. For instance, glutamate released from nerve terminals activates metabotropic glutamate receptors (mGluRs) on gastric cancer cells, triggering downstream MAPK and PI3K/AKT pathways that promote proliferation and resistance to apoptosis. Similarly, noradrenaline released from sympathetic nerve endings engages β-adrenergic receptors on tumor cells, activating cAMP/PKA signaling that enhances migratory capacity and metastatic potential [57].

The formation of neuro-tumor synapses is coordinated by adhesion molecules such as neuroligins and neurexins, which promote tight facilitate membrane apposition between nerve terminals and cancer cells. These molecular bridges are often overexpressed in innervated gastric tumors and correlate with perineural invasion—a histopathological feature associated with poor prognosis. Additionally, gap junctions composed of connexin proteins allow for direct ion and small molecule exchange between neurons and cancer cells, generating an electrically coupled network that synchronizes tumor cell behavior [58]. This synaptic mimicry enables cancer cells to co-opt neural circuits typically reserved for interneuronal communication, effectively turning nerves into conduits for protumor signaling.

Single-cell RNA sequencing studies have identified subsets of gastric cancer cells that express synaptic proteins typically restricted to neurons, including synaptophysin and postsynaptic density protein 95 (PSD-95). This “neuronal mimicry” suggests an evolutionary adaptation by which cancer cells optimize their ability to receive and process neural signals. Therapeutically, disrupting neuro-tumor synapses with targeted inhibitors of glutamatergic receptors or adrenergic signaling has shown promise in preclinical models, reducing tumor growth and neural invasion. However, selectively blocking these synapses without perturbing physiological neural function in healthy tissues remains a key challenge.

Neurotrophic Factors and Neural Infiltration in Gastric Cancer

Neurotrophic factors, particularly NGF and BDNF, serve as key mediators of neural infiltration in gastric cancer. Produced by tumor cells and stromal elements, these proteins establish chemotactic gradients that guide axonal growth toward and within the tumor.

NGF–TrkA Signaling in Neural Invasion and Tumor Progression

NGF, signaling through its high-affinity receptor tropomyosin receptor kinase A (TrkA)and the pan-neurotrophin receptor p75NTR, not only attracts sensory and sympathetic nerve fibers but also directly stimulates cancer cell proliferation and survival via PI3K/AKT and NF-κB activation. In gastric cancer, NGF expression correlates with the density of tumor-associated nerves and the degree of perineural invasion, highlighting its potential role as a biomarker of aggressive disease.

BDNF–TrkB Signaling and Dual Innervation

BDNF, acting through tropomyosin receptor kinase B (TrkB)receptors, exhibits complementary effects by promoting the outgrowth of enteric neurons that infiltrate gastric tumors. Unlike NGF, which primarily recruits extrinsic nerves, BDNF appears crucial for the expansion of intrinsic enteric nervous system fibers within the tumor microenvironment. This dual innervation—from both extrinsic and intrinsic sources—creates a dense neural network that supports tumor progression through multiple mechanisms. BDNF-TrkB signaling also protects cancer cells from anoikis (detachment-induced cell death), facilitating metastatic dissemination along nerve tracts [59].

Regulation of Neurotrophic Signaling and Therapeutic Targeting

The production of neurotrophic factors by gastric cancer cells is frequently stimulated by hypoxia and inflammatory cytokines, establishing a feed-forward loop in which tumor hypoxia induces NGF and BDNF secretion that, in turn, promotes nerve infiltration and the release of additional growth-promoting neurotransmitters. This self-reinforcing cycle underscores the therapeutic potential of targeting neurotrophic signaling. Monoclonal antibodies against NGF and small-molecule Trk inhibitors have demonstrated efficacy in preclinical gastric cancer models, reducing neural invasion and tumor progression. However, their clinical application requires careful consideration of potential neurological adverse effects, given the pleiotropic roles of neurotrophins in normal nervous system function.

Immunomodulatory Effects of Neurotrophic Factors

Neurotrophic factors also modulate the immune landscape in gastric tumors. NGF can polarize macrophages toward an immunosuppressive M2 phenotype, whereas BDNF has been shown to inhibit cytotoxic T-cell activity. These immunomodulatory effects underscore how neural infiltration can establish an immune-privileged niche that favors tumor progression. Current research is exploring combination therapies that simultaneously target neurotrophic signaling and immune checkpoints to disrupt both the neural and immunosuppressive components of the tumor microenvironment.

Clinical Implications and Future Directions

The clinical implications of tumor innervation are profound. Histopathological measures of neural density and perineural invasion status are increasingly recognized as independent prognostic factors in gastric cancer. Moreover, positron emission tomography (PET) radiotracers targeting neurotrophin receptors may soon enable noninvasive mapping of tumor innervation patterns, potentially for patient selection and treatment planning. As cancer neuroscience advances, therapies targeting the neural ecosystem of tumors may become integral to precision oncology approaches for gastric cancer. Future priorities include delineating the heterogeneity of tumor-associated nerves and engineering biomaterials for local delivery of neuromodulators to minimize systemic toxicity [60].

This evolving paradigm casts nerves as active components of the tumor microenvironment and opens therapeutic opportunities to disrupt reciprocal signaling between neurons and cancer cells. By targeting the molecular mechanisms of innervation, we may not only inhibit tumor progression but also prevent the debilitating pain associated with neural invasion in advanced gastric cancer (Table 2).

Neural signaling exerts profound and cell-type-specific effects on tumor-infiltrating immune populations through both neurotransmitter-mediated pathways and neuropeptide-receptor interactions. Macrophages, as key orchestrators of the tumor microenvironment, demonstrate remarkable plasticity in response to neural inputs. Catecholamines from sympathetic nerves polarize macrophages toward an M2-like phenotype via β2-adrenergic receptor (β2-AR) signaling in preclinical models, resulting in increased production of immunosuppressive cytokines (interleukin-10 [IL-10], transforming growth factor–β, [TGF-β]) and decreased antigen presentation capacity [72]. This adrenergic skewing is further enhanced by neuropeptide Y (NPY) in vitro and in vivo, which synergizes with catecholamines to upregulate arginase-1 expression, promoting tumor-associated macrophage (TAM) differentiation. Conversely, parasympathetic acetylcholine signaling throughα7nAChR has been shown in organoid/ex vivo and murine systems to attenuate M1 response, often tilting established tumors toward tolerance [73].

T cell populations are highly susceptible to neural modulation. Sympathetic overactivation induces CD8⁺ T cell exhaustion through cAMP-PKA pathway activation, characterized by increased expression of inhibitory receptors (programmed cell death protein 1 [PD-1], T cell immunoglobulin and mucin-domain containing-3 [TIM-3]) and impaired cytotoxic function. By contrast, β-adrenergic (β-AR) signaling expands and activates regulatory T cells (Tregs), enhancing their suppressive capacity through FoxP3 upregulation. The neurotransmitter dopamine presents an intriguing exception, exhibiting dual context-dependent effects—while low doses suppress T cell activation, physiological concentrations may actually enhance CD8⁺ T cell memory formation, suggesting a potential therapeutic opportunity for optimized dosing strategies [74].

MDSCs are particularly sensitive neural targets in gastric cancer. SP signaling through NK1R not only recruits MDSCs to tumors but also augments their suppressive activity by upregulating arginase-1 and inducible nitric oxide synthase (iNOS). This SP-MDSC axis establishes a feed-forward loop, as MDSC-derived IL-6 further stimulates neuronal outgrowth and neuropeptide release. The resulting neural-immune circuit represents a formidable barrier to effective anti-tumor immunity and may contribute to the limited efficacy of current immunotherapies in gastric cancer.

Beyond direct immune cell modulation, neural signals significantly influence the expression of immune checkpoint molecules that govern tumor-immune interactions. Norepinephrine upregulates PD-L1 on gastric cancer cells and antigen-presenting cells in preclinical models via β-AR–cAMP–CREB signaling, contributing to a ‘cold’ TME. This adrenergic-PD-L1 axis, supported by preclinical evidence, operates independently of interferon-γ signaling, representing an alternative mechanism of immune checkpoint regulation that may require combined β-blockade and PD-1/PD-L1 inhibition for optimal disruption.

Neuropeptides also reshape the immune-checkpoint landscape. Vasoactive intestinal peptide (VIP) induces PD-L1 and CTLA-4 on dendritic cells while simultaneously downregulating co-stimulatory molecules (CD80, CD86), effectively impairing T-cell priming. In gastric cancer specimens, VIP-positive nerve fibers show striking spatial colocalization with PD-L1+ tumor regions, suggesting local neural control of immune evasion. Similarly, CGRP upregulates multiple checkpoints (PD-L1, LAG-3) on myeloid cells through CLR/RAMP receptor signaling, creating a multi-inhibitory environment.

The clinical implications of these findings are substantial. Preclinical models indicate that pharmacological β-blockademay enhance the activity of anti-PD-1 therapy in gastric cancer, while antagonism of the SP receptor reduces MDSC accumulation and checkpoint expression. Emerging evidence suggests that neural regulation of immune checkpoints can contribute to the development of immunotherapy resistance, as denervation experiments show restored sensitivity to checkpoint blockade in previously refractory tumors. Current clinical trials are exploring these neuro-immune interactions with combination regimens that target both neural signaling and immune checkpoints, and early reports describe improved response rates relative to monotherapy.

Technological advances are rapidly deepening our understanding of neuro-immune crosstalk. Spatial transcriptomics delineates anatomical relationships between nerve fibers and immune-cell clusters within gastric tumors, while optogenetic tools allow precise manipulation of neural activity to study real-time immune consequences. Together, these approaches reveal marked heterogeneity in neuro-immune interactions across gastric-cancer subtypes, suggesting future therapeutic strategies may require personalized neuromodulation tailored to tumor innervation patterns and immune profiles [75]. As the field progresses, targeting the neuro-immune axis may provide a crucial avenue for overcoming the current limitations of gastric cancer immunotherapy (Table 3).

Chronic stress activates the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system, driving sustained secretion of glucocorticoids (primarily cortisol) and catecholamines (norepinephrine and epinephrine). These stress hormones remodel the gastric tumor microenvironment through multiple, parallel mechanisms. Cortisol exerts immunosuppressive effects predominantly via the glucocorticoid receptor, inducing transcriptional programs in immune cells that favor tumor immune evasion. MDSCs show particular sensitivity to glucocorticoid signaling, with cortisol promoting their expansion and enhancing their immunosuppressive capacity through upregulation of arginase-1 and inducible nitric oxide synthase. The differentiation and function of dendritic cells are similarly impaired, resulting in deficient antigen presentation and reduced T cell priming. Natural killer cells, critical mediators of tumor immune surveillance, exhibit decreased cytotoxic activity and interferon-γ production under chronic glucocorticoid exposure. Perhaps most significantly, the T cell compartment undergoes dramatic reprogramming, with cortisol promoting regulatory T cell (Treg) expansion while inhibiting Th1 differentiation and CD8⁺ T cell effector function. Collectively, this hormonal modulation establishes an immune-tolerant microenvironment that permits tumor progression. Complementing these effects, catecholamines exert acute immunosuppression actions through β-adrenergic receptor signaling. Norepinephrine and epinephrine activate the cAMP-PKA pathway in macrophages, biasing polarization toward an M2-like phenotype characterized by increased IL-10 and TGF-β secretion. In T lymphocytes, chronic adrenergic signaling promotes an exhaustion phenotype with co-expression of multiple inhibitory receptors, including PD-1, TIM-3, and LAG-3. The discovery that β-adrenergic signaling can directly upregulate PD-L1 on both tumor cells and myeloid cells through CREB-dependent transcription provides a mechanistic link between stress and immunotherapy resistance. Clinical observations support these experimental findings, with elevated stress hormone levels correlating with poorer responses to immune checkpoint inhibitors in gastric cancer patients.

Beyond endocrine mechanisms, chronic stress induces persistent neuroinflammation that further facilitates immune evasion in gastric cancer. This neuroinflammatory cascade begins with microglial activation in stress-responsive brain regions and is accompanied by increased production of proinflammatory cytokines, including IL-1β, TNF-α, and IL-6. These cytokines enter systemic circulation and infiltrate the tumor microenvironment, where they activate NF-κB and STAT3 signaling pathways in both tumor and stromal cells. The resulting inflammatory milieu promotes recruitment and activation of immunosuppressive cell populations while inhibiting effective anti-tumor immunity [88].

Sensory neurons within and around gastric tumors amplify inflammatory signaling by releasing neuropeptides such as SP and CGRP. SP, acting through neurokinin-1 receptors, induces pro-tumorigenic cytokines and chemokines while directly inhibiting T cell activation. CGRP exerts complementary effects by promoting the differentiation and recruitment of regulatory T cells and tolerogenic dendritic cells. Together, these neuropeptides sustain a self-reinforcing neurogenic inflammation loop that maintains an immune-permissive milieu [75].

The gut-brain axis further modulates neuroinflammatory through bidirectional communication between the enteric nervous system and central stress circuits. Stress-induced alterations in gut permeability and shifts in microbiota composition heighten systemic exposure to microbial products, thereby amplifying peripheral inflammation and neuroimmune activation. In gastric cancer, these changes manifest as elevated production of damage-associated molecular patterns and activation of pattern recognition receptors that can promote tumor progression.

Emerging therapeutic strategies aim to interrupt these stress-induced immunosuppressive pathways. β-adrenergic blockade has shown promise in preclinical models by restoring immune function and enhancing checkpoint inhibitor efficacy. Similarly, pharmacological modulation of neuropeptide signaling and targeted anti-inflammatory approaches may help break the cycle of neurogenic immunosuppression. Development of biomarkers to identify patients with stress-related immune dysfunction could enable more personalized treatment in gastric cancer [89].

Emerging insights into the microbiota-gut-brain axis implicate it in gastric cancer development through complex, bidirectional communication among intestinal microbes, the enteric nervous system, and central neural circuits. This trilateral network influences gastric tumor immunology through neural and humoral pathways, helping establish a microenvironment that shapes tumor progression and therapeutic responsiveness. The vagus nerve is the principal anatomical conduit for gut-brain communication, with afferent fibers transmitting microbial signals from the gastrointestinal tract to the central nervous system and efferent fibers carrying regulatory inputs back to the gut-associated lymphoid tissue [90]. Specific gut microbiota compositions can modulate gastric cancer immunity through vagus nerve-dependent mechanisms, where microbial metabolites such as short-chain fatty acids (SCFAs) and secondary bile acids activate enteric neurons that subsequently influence tumor-infiltrating immune cells. Butyrate-producing bacteria, for instance, stimulate vagal afferents that trigger anti-inflammatory responses in the gastric tumor microenvironment, while certain pathogenic species activate sympathetic outflow that suppresses cytotoxic T cell activity. This microbial-neural-immune crosstalk forms a dynamic regulatory system in which dysbiosis may promote tumor immune evasion through functional rewiring of neural circuits [91].

Helicobacter pylori infection provides a particularly compelling example of neuro-immune interactions in gastric carcinogenesis. Beyond its established role in driving chronic inflammation and epithelial damage, H. pylori engages in sophisticated dialogue with both the enteric and central nervous systems. The bacterium produces virulence factors such as vacuolating cytotoxin A (VacA) and cytotoxin-associated gene A (CagA) that directly interact with enteric neurons, altering their excitability and neurotransmitter release profiles. These neural modifications subsequently influence the gastric immune landscape, with H. pylori-infected neurons releasing SP and calcitonin gene-related peptide that recruit immunosuppressive myeloid cells while inhibiting protective T cell responses [92]. Infection also induces structural plasticity of gastric innervation, increasing the density of sensory fibers that can sustain inflammatory signaling even after bacterial eradication. Notably, H. pylori can modulate central stress response pathways through vagus-mediated signaling, creating a feedback loop where psychological stress exacerbates infection-related carcinogenesis and vice versa. This neuro-immune interplay may help explain the variable outcomes of H. pylori infection, where some individuals develop protective immunological tolerance while others progress to premalignant lesions and eventually gastric adenocarcinoma [93].

The gut microbiome further shapes gastric-cancer progression through its metabolic output, with various microbial metabolites directly affecting neural function and immune regulation. Tryptophan metabolites along the kynurenine pathway, for example, act as mediators of this cross-talk by engaging aryl-hydrocarbon receptors on neural and immune cells and by modulating immune checkpoints to foster an immunosuppressive niche [93]. Gamma-aminobutyric acid (GABA) produced by gut bacteria can similarly modulate tumor-associated macrophages through GABA receptor signaling while simultaneously influencing central neural circuits involved in stress response. Collectively, these position the microbiota-gut-brain axis as an integrative regulator of gastric cancer immunology, in which microbial, neural, and immune factors coalesce to determine tumor fate.

Therapeutic manipulation of this axis through probiotics, vagus nerve stimulation, or microbial metabolite supplementation represents a promising frontier in gastric cancer treatment, potentially offering ways to overcome current limitations in immunotherapy efficacy [94]. Recognition of these complex interactions underscores the need for a more holistic approach to gastric-cancer management that considers not just the tumor itself but its broader neuroimmune and microbial context [95]. Fig. 2 illustrates the complex bidirectional communication within the microbiota–gut–brain axis and its impact on gastric cancer pathogenesis.

Heterogeneous PD-L1 expression across gastric cancer subtypes contributes to substantial variability in treatment responses. While the combined positive score (CPS) serves as a companion diagnostic, its predictive value is imperfect, and marked response heterogeneity persists even among CPS-positive patients. Diffuse-type carcinomas consistently fare worse than intestinal-type tumors after checkpoint inhibition, likely reflecting distinct microenvironment composition and lower immunogenicity. Tumor mutational burden, while predictive in some cancer types, demonstrates inconsistent correlation with immune therapy benefit in gastric cancer, partially because the specific mutagenic processes underlying different etiological subtypes (EBV-positive vs microsatellite unstable tumors) create divergent immunological contexts. The characteristic immunosuppressive tumor microenvironment of gastric cancer, rich in regulatory T cells, myeloid-derived suppressor cells, and M2-polarized macrophages, establishes multiple layers of immune resistance that single-agent checkpoint inhibition frequently fails to overcome [96].

Emerging evidence identifies the nervous system as a critical mediator of immunotherapy resistance through multifaceted biological mechanisms. Neuron-derived signals actively remodel the tumor immune microenvironment in ways that counteract the intended effects of immune checkpoint blockade. Catecholamines released from sympathetic nerve terminals engage β-adrenergic receptors on immune and tumor cells, activating parallel immunosuppressive pathways that undermine PD-1/PD-L1 inhibition [97]. This adrenergic signaling induces compensatory expression of alternative immune checkpoints, including LAG-3 and TIM-3 on exhausted T cells while simultaneously expanding immunosuppressive myeloid populations [98].

Neuropeptide signaling imposes additional barriers to effective immunotherapy. SP and vasoactive intestinal peptide modulate dendritic cell function and promote regulatory T cell activity through distinct receptor-mediated pathways. The vagus nerve exerts immunosuppressive effects in the gastric microenvironment through cholinergic signaling that suppresses pro-inflammatory cytokine production and limits T cell activation. Preclinical models demonstrate that PD-1 blockade triggers compensatory increases in neural outgrowth and neurotransmitter release, suggesting an active neural response to immune activation [99].

The gut-brain axis contributes significantly to immunotherapy resistance through microbial-neural-immune interactions that are particularly relevant in gastric cancer. Specific gut microbiota compositions associated with poor responses appear to promote sympathetic tone and neuroinflammatory states that reinforce immune tolerance. Persistent Helicobacter pylori infection maintains chronic, low-grade inflammation and neural remodeling, thereby fostering an immunotherapy-resistant microenvironment. The enteric nervous system mediates this process by transmitting microbial signals to central neural circuits that subsequently modulate systemic immune responses through neuroendocrine pathways.

These complex neuro-immune interactions help explain both the modest initial response rates and the frequent loss of response to current immunotherapies. They imply that successful treatment strategies may require simultaneous targeting of both immune checkpoints and neural signaling pathways. Ongoing clinical trials investigating combinations of PD-1/PD-L1 inhibitors with β-adrenergic blockers, neurokinin receptor antagonists, and vagus nerve modulators may provide critical proof-of-concept for this integrated therapeutic approach. Developing reliable biomarkers to identify patients with neural-mediated resistance mechanisms represents another crucial direction for future research in this field [100].

The growing understanding of neural regulation in gastric cancer has identified several neurotransmitter receptors as promising therapeutic targets. β-adrenergic receptor blockade has emerged as a particularly compelling strategy, with preclinical studies demonstrating that drugs like propranolol can reverse catecholamine-mediated immunosuppression and enhance PD-1 inhibitor efficacy. Proposed mechanisms include reduced MDSC infiltration, decreased regulatory T-cell (Treg) activity, and normalization of aberrant tumor vasculature [101]. Clinical trials are currently investigating β-blockers in combination with immune checkpoint inhibitors for gastric cancer. Similarly, cholinergic antagonists targeting α7 nicotinic acetylcholine receptors (α7nAChR) show potential to mitigate the immunosuppressive effects of vagus nerve signaling [102]. These drugs appear to restore dendritic cell function and improve CD8⁺ T cell infiltration in gastric cancer models. The timing and dosing of these neuromodulatory agents relative to immunotherapy appear crucial, with some studies suggesting pretreatment with neural-targeting drugs may be necessary for optimal immune activation [103].

SP/NK-1R signaling is increasingly recognized as a key pathway in gastric cancer progression and immune evasion. NK-1 receptor antagonists like aprepitant, originally developed as antiemetics, have demonstrated multifaceted antitumor effects in preclinical models [104]. These drugs not only curb cancer cell proliferation and migration but also significantly alter the immune landscape by decreasing MDSC accumulation and improving cytotoxic T cell function. In gastric cancer models, NK-1R blockade has been shown to reduce PD-L1 expression on tumor cells while increasing interferon-γ production by tumor-infiltrating lymphocytes. Other neuropeptide systems under investigation include CGRP receptor antagonists, which have shown potential to normalize tumor vasculature and reduce macrophage-mediated immunosuppression. Interestingly, some neuropeptide inhibitors appear to have direct effects on cancer stem-like cells, suggesting they may help prevent recurrence [105]. Optimal combinations with conventional therapies—and their impact on chemotherapy-induced neuropathy—remain active areas of investigation [106].

Surgical and chemical denervation are being revisited for their capacity to reprogram the tumor-immune microenvironment in the cancer. In preclinical models, vagotomy or selective denervation is associated with reduced tumor growth, greater CD8⁺ T-cell infiltration, and lower Treg abundance, effects consistent with attenuation of cholinergic immunomodulatory inputs and decreased neurotrophic drive, such as nerve growth factor. Chemical denervation with botulinum toxin has yielded comparable signals in selected settings and is potentially reversible [107]. However, the timing and extent of denervation appear critical, as complete autonomic disruption can have unintended consequences on gastrointestinal function and may paradoxically activate alternative immunosuppressive pathways. Emerging techniques like focused ultrasound and radiofrequency ablation offer more targeted approaches to modulate specific nerve populations without complete disruption. These approaches are being explored in combination with immunotherapy, with early-phase clinical trials investigating whether localized nerve modulation can enhance checkpoint inhibitor efficacy while minimizing systemic side effects. The development of nerve-sparing techniques that selectively target tumor-associated nerves while preserving normal autonomic function represents an important direction for future research (Fig. 3). Specificity can be enhanced by nerve-sparing trajectories, receptor-pathway selection, and stage-aware timing that prioritizes tumor-proximal plexuses [108,109]. Safety remains central: extensive denervation may impair motility or bile reflux control and can induce dumping-like syndromes or collateral injury [110]; early studies should incorporate objective target-engagement and pharmacodynamic readouts (heart-rate variability, tissue/serum norepinephrine, tyrosine-hydroxylase–positive fiber density, pathway activation), standardized safety monitoring (orthostatic vitals, rhythm surveillance, gastric emptying), and predefined stopping rules [111]. These procedures are being prospectively combined with immune-checkpoint blockade to test whether localized neuromodulation improves efficacy while limiting systemic adverse effects, and nerve-sparing techniques that selectively address tumor-associated nerves represent a pragmatic direction for near-term clinical translation. Fig. 3 illustrates strategies that target the neuro-immune axis to enhance immunotherapy in gastric cancer.