Research progress on chronic stress stimulation and gastric cancer metastasis

Abstract

Gastric cancer remains a major clinical challenge due to its propensity for metastasis and poor five-year survival rates. Emerging evidence implicates chronic psychological stress as a critical promoter of tumor dissemination. Stress signals engage both the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS), leading to sustained elevations of cortisol and catecholamines. These mediators act on glucocorticoid receptors (GR) and β-adrenergic receptors (ADRB2) in gastric cancer cells, thereby activating downstream cAMP/PKA and NF-κB/STAT3 pathways. The resulting cascade enhances epithelial–mesenchymal transition (EMT), upregulates matrix metalloproteinases, and promotes neovascularization, while concurrently inducing an immunosuppressive microenvironment characterized by CD8⁺ T-cell exhaustion, M2-polarized TAMs, and Treg expansion. Moreover, stress-driven epigenetic and metabolic reprogramming amplifies the Warburg effect and synergizes with Helicobacter pylori infection to accelerate tumor invasion. Clinical and cohort studies consistently associate elevated stress markers with increased metastasis risk, and interventions—ranging from β-blockers and GR antagonists to cognitive-behavioral therapy—show promise in mitigating these effects. Future advances in multi-omics, spatial profiling, smart probiotics, and optogenetic tools are poised to unravel the complex “stress-tumor” interface and enable precise, integrative mind-body therapeutic strategies.

Introduction

Gastric cancer is a malignant tumor that poses a serious threat to human health worldwide. According to global cancer statistics for 2022, there were approximately 1.09 million new cases of gastric cancer and 770,000 deaths, ranking fifth in incidence and fourth in mortality among all cancers. The five-year survival rate is less than 30%. China accounts for 43.9% of global new cases (2020 data) [1]. Tumor metastasis is the primary determinant of poor prognosis and patient mortality in clinical practice [2, 3]. In the context of increasing psychological stress in modern society, chronic stress has emerged as a significant environmental carcinogenic and tumor-promoting factor [4–6], and research on its association with tumor metastasis has become a cutting-edge hotspot in cancer research [7, 8]. Chronic stress not only stems from the psychological burden caused by the disease itself but is also closely related to social factors such as accelerated modern lifestyles and intensified occupational competition, forming a unique “stress-tumor” vicious cycle. Recent studies have shown that chronic stress profoundly influences the tumor microenvironment through multidimensional regulation of the neuroendocrine-immune network [9, 10]. Continuous activation of the sympathetic nervous system leads to abnormal secretion of stress hormones such as epinephrine and norepinephrine [11–13]. These molecules act on β-adrenergic receptors (β-AR) on the surface of tumor cells, activating key signaling pathways such as JAK-STAT3 and promoting the epithelial-mesenchymal transition (EMT) process [14]. Animal experiments have shown that chronic restraint stress can upregulate the expression of pro-metastatic factors such as MMP-9 and VEGF by 3–5 times in gastric cancer xenograft models and significantly enhance the invasive and metastatic capabilities of tumor cells toward the peritoneum and liver [15]. Notably, stress-induced immune remodeling is equally significant: elevated cortisol levels lead to CD8 + T cell functional exhaustion, polarization of tumor-associated macrophages (TAMs) toward the M2 phenotype, and abnormal accumulation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment, collectively establishing an immunosuppressive niche [16]. Similar conclusions have been drawn from studies on chronic adrenergic stress [17]. Although significant progress has been made in basic research, the integrated mechanisms by which stress influences gastric cancer metastasis remain largely unexplored. First, does the regulation of tumor metastasis exhibit heterogeneity depending on the type of stress (psychological vs. physiological) [18, 19]? Second, how do stress signals interact synergistically with tumor gene mutations (such as TP53 dysfunction [20], HER2 amplification, and nuclear localization [21], etc.)? Furthermore, what role does chronic stress-induced metabolic reprogramming of gastrointestinal tumors (such as enhanced glycolysis [22] and abnormal glutamine metabolism [23]) play in the metastasis process? Resolving these scientific questions is crucial for developing precise intervention strategies. Previous studies have discussed the bidirectional causal relationship between gastric cancer and chronic stress [24]. Clarifying the complex relationship between chronic stress stimulation and gastric cancer progression is essential for formulating effective treatment strategies and improving the overall prognosis of patients facing this complex disease. However, specific target mechanisms and individualized application protocols still require systematic validation. Herein, we systematically review recent advances elucidating how chronic stress promotes gastric cancer metastasis through molecular interactions, immune editing, and metabolic regulation. By integrating findings across multiple levels, we aim to provide a comprehensive theoretical framework to guide the design of mind-body combined therapeutic strategies that mitigate stress-driven tumor progression.

Core mechanisms of gastric cancer metastasis

Gastric cancer cell invasion and migration

The epithelial-mesenchymal transition (EMT) represents a fundamental biological mechanism through which gastric cancer cells penetrate the basement membrane barrier and acquire invasive properties [25–27]. This process is meticulously regulated by transcription factors, including Snail, Slug, and Twist [28–30]: specifically, Snail recruits the histone demethylase LSD1 to selectively remove the H3K4me2 active mark from the E-cadherin promoter region, thereby inducing its epigenetic silencing. Concurrently, Snail activates the expression of mesenchymal markers such as N-cadherin and vimentin, resulting in the loss of cellular polarity and the acquisition of migratory capabilities. Single-cell sequencing data indicate that the expression heterogeneity of EMT-related genes in gastric cancer metastases is notably higher than in primary tumors, with Twist1-positive cell subpopulations constituting 38% and demonstrating a positive correlation with circulating tumor cell (CTC) numbers (r = 0.65, P < 0.001) [31].Importantly, the EMT process is intricately linked to tumor stemness characteristics: CD44 + gastric cancer stem cells sustain ZEB1 expression via the Wnt/β-catenin pathway, thereby establishing a self-renewing reservoir of metastatic initiator cells [32]. The matrix metalloproteinase (MMP) family serves as the principal mediator of extracellular matrix (ECM) degradation [33, 34]. Specifically, MMP-2 and MMP-9, secreted by gastric cancer cells, facilitate the hydrolysis of type IV collagen and laminin, thereby generating physical pathways conducive to cell migration. Notably, membrane-type MMP (MT1-MMP) is instrumental in this process by activating the pro-MMP-2 precursor, and the ablation of MT1-MMP has been shown to diminish the capacity of gastric cancer cells to invade Matrigel [35, 36]. Clinical pathological analyses indicate that serum MMP-7 levels exceeding 12 ng/mL in gastric cancer patients are associated with a significantly elevated risk of peritoneal metastasis [37]. Furthermore, MMPs contribute to a positive feedback loop that enhances tumor metastasis by releasing growth factors sequestered within the ECM, such as TGF-β and FGF2 [38, 39].

Vascular/lymphatic vessel formation

Vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) form the central axis of angiogenesis [40, 41]. Under conditions of chronic stress, adrenaline and noradrenaline released from sympathetic nerve endings activate hypoxia-inducible factor 1-alpha (HIF-1α) via β2-adrenergic receptors (ADRB2). This activation leads to the binding of HIF-1α to the hypoxia response element (HRE) within the VEGF promoter, resulting in a 2–3fold increase in its transcriptional activity [42, 43]. Clinical studies have demonstrated a significant positive correlation between serum VEGF levels and stress scores (PSS-10) in patients with gastric cancer (r = 0.58, P = 0.004). Furthermore, the incidence of liver metastasis is 3.1 times higher in the high VEGF expression group (>450 pg/mL) compared to the control group, with a correspondingly poorer prognosis [44]. In animal models, the use of the ADRB2 antagonist propranolol resulted in a 58% reduction in microvascular density within transplanted tumors and inhibited the spread of tumor cells to the portal vein [45]. IL-8 (CXCL8) facilitates metastasis through a dual mechanism: it activates the CXCR2 receptor on endothelial cells, leading to a 2.4-fold increase in vascular permeability [46], Secondly, it promotes tumor cell motility via autocrine signaling mechanisms [47]. Single-cell transcriptomic analysis has demonstrated that in gastric cancer cell subpopulations with high IL-8 expression, genes associated with actin rearrangement, including RhoA and ROCK1, are upregulated by 4 to 6 times, and the frequency of pseudopod formation increases threefold [48]. Furthermore, the stress-induced neuropeptide substance P (SP) can synergistically activate the NF-κB pathway in conjunction with IL-8, creating a detrimental cycle of pro-inflammatory and pro-angiogenic effects [49].

Immune escape

The PD-L1/PD-1 axis represents a fundamental mechanism of immune evasion in gastric cancer [50]. Interferon-γ (IFN-γ) upregulates PD-L1 expression through the JAK1/STAT1 signaling pathway, while cortisol, produced in response to chronic stress, further amplifies this effect via the glucocorticoid receptor (GR). Under simultaneous stimulation, PD-L1 protein levels can increase by up to 5.7-fold compared to single stimulation [51]. Epigenetic studies have demonstrated that cancer patients exhibiting low DNA methylation (methylation rate < 15%) in the PD-L1 promoter region show significantly enhanced response rates to PD-1 inhibitors (objective response rate [ORR] 42% versus 11%, P = 0.002) [52]. T cell exhaustion is characterized by a loss of effector function and persistent expression of inhibitory receptors such as PD-1, TIM-3, and LAG-3 [53]. In models of chronic stress, the mitochondrial function of CD8 + T cells is compromised, with ATP production decreasing by 60%, and the phosphorylation level of ZAP-70, a critical protein in T cell receptor (TCR) signaling, is reduced by 75% [54]. Concurrently, regulatory T cells (Tregs) promote tumor metastasis by secreting IL-10 [55] and TGF-β [56].This results in the formation of an immunosuppressive microenvironment. Notably, when the infiltration density of FoxP3 + regulatory T cells (Tregs) in gastric cancer tissue surpasses 50 cells per high-power field (HPF), the 5-year survival rate of patients significantly decreases from 38% to 12% (P < 0.001) [57]. Recent research has demonstrated that stress-induced neuropeptide Y (NPY) can directly activate the Y1 receptor on the surface of Tregs, thereby augmenting their immunosuppressive function, as evidenced by a 2.8-fold increase in interleukin-10 (IL-10) secretion [58].

The physiological and molecular basis of chronic stress

Neuroendocrine activation

HPA axis and cortisol: Chronic stress initiates the activation of the hypothalamic-pituitary-adrenal (HPA) axis [59], resulting in prolonged secretion of glucocorticoids, predominantly cortisol. Stress signals are conveyed from the amygdala to the paraventricular nucleus (PVN) of the hypothalamus, where corticotropin-releasing hormone (CRH) stimulates the anterior pituitary gland to release adrenocorticotropic hormone (ACTH). This cascade ultimately leads to a two-to-three-fold increase in cortisol synthesis by the adrenal cortex. Clinical cohort studies have demonstrated that in breast cancer patients, serum cortisol levels exceeding 20 µg/dL correlate with a 58% reduction in CD8 + T cell infiltration density, alongside a decrease in the five-year survival rate from 42% to 19% (P < 0.001) [19]. Mechanistically, the cortisol-glucocorticoid receptor (GR) complex binds directly to the glucocorticoid response element (GRE) of the CD3ε gene, a component of T cell receptor (TCR) signaling, thereby inhibiting its transcriptional activity while simultaneously inducing a 2.1-fold upregulation of PD-1 expression [60]. In contemporary research, the sympathetic nervous system and catecholamines, specifically norepinephrine (NE) and epinephrine (Epi), are recognized for their role in activating tumor cell signaling predominantly through the β2-adrenergic receptor (ADRB2) [61, 62]. As a G protein-coupled receptor (GPCR), ADRB2 interacts with the Gαs protein to stimulate adenylate cyclase (AC), resulting in a 10–15-fold increase in intracellular cAMP concentration within five minutes [63]. Animal studies have demonstrated that in a chronic restraint stress mouse model, the use of the ADRB2 antagonist propranolol significantly reduces tumor metastasis [64]. Furthermore, epigenetic analyses have shown that prolonged stimulation by epinephrine leads to hypomethylation of the ADRB2 promoter region, decreasing the methylation rate from 68% to 24%, thereby establishing a positive feedback loop that enhances receptor expression [65].

Key signaling pathways

The cAMP/PKA signaling pathway involves the activation of the catalytic subunit of protein kinase A (PKAc) by cyclic adenosine monophosphate (cAMP), which subsequently phosphorylates the transcription factor CREB at the Ser133 site, thereby promoting the transcription of MMP-9 and CXCR4 genes [66, 67]. Advanced single-molecule tracking techniques have demonstrated that PKA forms nanoscale signaling clusters at the cell periphery. These clusters can be anchored to membrane microdomains through β-arrestin2, facilitating the polarized transmission of signals that direct cell migration [68]. Moreover, the activation of ADRB2 has been shown to enhance cell-matrix adhesion, increasing the adhesion spot area by 1.8-fold via the Epac/Rap1 pathway, independently of PKA [69]. Regarding the NF-κB and STAT3 pathways, stress hormones activate NF-κB through a dual mechanism: norepinephrine (NE) phosphorylates IκBα at the Ser32/36 sites via the ADRB2-PKCθ pathway, leading to its degradation and the release of the p65/p50 dimer [15]; concurrently, cortisol induces the expression of TRAF2 via the glucocorticoid receptor (GR), thereby augmenting TNFR signaling [70]. The activated NF-κB and STAT3 proteins form a transcriptional complex that jointly regulates the expression of pro-metastatic factors such as IL-6 and VEGF [71, 72]. Protein interaction mass spectrometry analysis shows that the SH2 domain of STAT3 can directly bind to the DNA-binding domain of GR, mediating the synergistic activation of the IL-6 promoter by glucocorticoids (luciferase activity increased by 4.3-fold) [72, 73]. This cross-talk enables gastric cancer cells to acquire stronger inflammatory tolerance and metastatic potential under stress conditions.

Major mechanistic axes of stress-driven gastric cancer metastasis

Neuroendocrine signaling and EMT

Chronic stress stimulation results in the activation of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis, thereby establishing a “dual-axis driven” pro-metastatic microenvironment. Norepinephrine (NE), serving as the primary neurotransmitter, initiates the Gαs-AC-cAMP signaling pathway via the β2-adrenergic receptor (ADRB2). Advanced single-molecule tracking techniques have demonstrated that ADRB2 forms dimers within the lipid rafts of the cell membrane. Upon NE binding, a conformational change is induced, reducing the dissociation time of the Gαs protein to 0.3 s, which leads to an approximately 12-fold increase in cAMP concentration within 5 min [63]. Cyclic adenosine monophosphate (cAMP) phosphorylates cAMP response element-binding protein (CREB) at serine 133 through protein kinase A (PKA), thereby enhancing the transcription of matrix metalloproteinases 2 and 9 (MMP2/9), which is evidenced by a 4.8-fold increase in mRNA levels. Additionally, cAMP upregulates the expression of critical epithelial-mesenchymal transition (EMT) regulators, Snail and Twist, with mRNA levels increasing by 3.6-fold and 3.1-fold, respectively. This regulatory cascade results in the downregulation of the cell adhesion molecule E-cadherin, with protein levels decreasing by approximately 65%, and the upregulation of N-cadherin and vimentin, thereby facilitating a phenotypic transition of gastric cancer cells from an epithelial to a mesenchymal state. Morphologically, this transition is characterized by elongated cellular spines and an increase in pseudopodia [25, 26]. Furthermore, the activation of the Epac/Rap1 pathway contributes to enhanced pseudopod formation, with pseudopod numbers increasing by 2.3-fold [48]. In vitro experiments demonstrated that treatment of gastric cancer cells with 10 µM norepinephrine for 48 h resulted in a significant increase in the number of Transwell migrating cells, from 85 ± 12 in the control group to 243 ± 29 (P < 0.001) [74]. Recent research underscores that stress hormones exert effects not only directly on tumor cells but also through modulation of the tumor stroma. Cancer-associated fibroblasts (CAFs), which constitute a significant component of the gastric tumor microenvironment, can be activated via β-adrenergic signaling to secrete extracellular vesicles (EVs) that are enriched with pro-metastatic microRNAs (miRNAs). These vesicles facilitate epithelial-mesenchymal transition (EMT) and angiogenesis in adjacent cancer cells. A notable study, titled “The Role of miRNAs in the Extracellular Vesicle-Mediated Interplay Between Breast Tumor Cells and Cancer-Associated Fibroblasts" [75], highlights the critical role of EV cargoes in orchestrating bidirectional communication between cancer and stromal cells, a mechanism that is likely conserved in gastric cancer.

Immune remodeling and tumor immune escape

Chronic stress impairs the anti-metastatic function of natural killer (NK) cells through a dual mechanism. Firstly, receptor modulation is observed, as evidenced by a 62% reduction in the expression of the NK cell surface activation receptor NKG2D and a 3.8-fold increase in the inhibitory receptor TIGIT in stress model mice, as validated by flow cytometry [76]. Secondly, mitochondrial damage is implicated, with cortisol inducing a 2.1-fold overexpression of the mitochondrial fission protein Drp1 via the glucocorticoid receptor (GR), resulting in mitochondrial fragmentation and a decrease in functional mitochondria from 75% to 32% [77]. Experimental studies in animals demonstrate that chronic restraint stress significantly reduces the cytotoxic efficiency of NK cells against gastric cancer cells, from 51 ± 6% in the control group to 17 ± 4% (P < 0.001) [78]. Epigenetic regulation of macrophage polarization is significantly influenced by stress signals, which induce M2 polarization through intricate metabolic-epigenetic interactions. Metabolic remodeling involves norepinephrine (NE) activating hypoxia-inducible factor 1-alpha (HIF-1α) via the beta-2 adrenergic receptor (ADRB2), thereby enhancing macrophage glycolysis and resulting in a 2.4-fold increase in lactic acid production. This acidic microenvironment subsequently upregulates the expression of arginase-1 (Arg1) [79]. Regarding epigenetic modification, the histone demethylase JMJD3 is responsible for removing H3K27me3 modifications following NE stimulation, leading to the activation of M2 markers, specifically CD206 and IL-10 genes, as validated by chromatin immunoprecipitation sequencing (ChIP-seq) [80]. Previous research has demonstrated that elevated JMJD3 expression in colorectal, breast, and liver cancers facilitates tumor proliferation and migration [81]. However, the precise mechanism by which JMJD3 affects migration in gastric cancer remains to be elucidated. Analysis of clinical samples indicates that when the M2/M1 macrophage ratio in gastric cancer tissue surpasses 2.5, the risk of liver metastasis increases by 4.1-fold (hazard ratio [HR] = 4.1, 95% confidence interval [CI] 2.3–7.4) [82]. Extracellular matrix remodeling involves stress-induced aberrant activation of the lysyl oxidase (LOX) enzyme family. Norepinephrine (NE) has been shown to upregulate LOX expression by 3.5-fold through the β2-adrenergic receptor (β2-AR)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway. This upregulation facilitates collagen cross-linking, resulting in an increase in matrix stiffness from 0.5 kPa to 1.7 kPa, as determined by atomic force microscopy [83]. The resultant matrix stiffening subsequently activates the integrin β1-focal adhesion kinase (FAK)-Yes-associated protein (YAP) signaling pathway, thereby enhancing the invasive capacity of gastric cancer cells, with invasion depth increasing by 2.8-fold in three-dimensional culture models [84].

Angiogenesis and Inflammation-driven

The positive feedback loop of VEGF signaling is influenced by stress hormones, which promote angiogenesis. Norepinephrine (NE) activates the ADRB2/cAMP/CREB signaling axis, resulting in a 3.2-fold increase in VEGF-A gene transcription, as evidenced by enhanced promoter luciferase activity [85]. Additionally, cortisol inhibits the expression of the VEGF-degrading enzyme MMP-14 via the glucocorticoid receptor (GR), leading to a 58% reduction in mRNA levels and extending the half-life of VEGF to 2.3 times that observed in the control group [86, 87]. Clinical imaging studies have demonstrated that microvascular density (MVD) in gastric cancer lesions is significantly elevated in patients experiencing chronic stress compared to the control group [88]. In the context of epithelial-mesenchymal transition (EMT), the integration of cytoskeletal remodeling and signaling pathways is evident. NE facilitates myosin II phosphorylation, with p-MLC levels increasing by 3.1-fold, through the RhoA/ROCK pathway, thereby promoting cell contraction and polarity establishment [89–91]. Furthermore, the cortisol-GR complex binds to the Snail promoter glucocorticoid response element (GRE), resulting in a 90% downregulation of E-cadherin expression, as confirmed by immunohistochemistry [92]. Single-cell sequencing has revealed that the proportion of hybrid EMT cells in gastric cancer cells derived from stress model mice reached 41%, representing a 3.8-fold increase compared to the control group [93]. The formation of cytokine storms is mediated by stress signals that activate the inflammatory network via two distinct pathways. Neuropeptide Y (NPY), released from sympathetic nerve terminals, engages the Y1 receptor on macrophages, thereby activating NF-κB and enhancing IL-6 secretion, with a reported 6.2-fold increase in concentration [94]. Concurrently, cortisol augments IL-6 signaling by facilitating the direct binding of the glucocorticoid receptor (GR) to STAT3, which extends the nuclear retention of STAT3 from 25 min to 68 min [72, 95]. Clinical cohort studies indicate that patients with gastric cancer exhibiting serum IL-6 levels exceeding 10 pg/mL have a 4.7-fold increased risk of peritoneal metastasis compared to controls (P = 0.003) [96]. The inflammatory-EMT cycle is perpetuated by IL-6, which sustains the epithelial-mesenchymal transition (EMT) phenotype through an autocrine mechanism. IL-6 activates STAT3, which not only induces its own expression (resulting in an 8-fold increase in autocrine levels) but also upregulates TGF-β1 expression (with a 3.3-fold increase in mRNA levels), establishing a positive feedback loop [97]. Furthermore, inflammatory mediators induce the expression of IDO1, which activates GCN2 kinase by depleting tryptophan, thereby promoting ATF4-dependent transcription of pro-metastatic genes [98].

Metabolic reprogramming and epigenetic memory

Stress-Enhanced Warburg Effect: Chronic stress has been shown to augment glycolysis through multifaceted regulatory mechanisms. Norepinephrine (NE) phosphorylates PFKFB3 at Ser461 via the β2-adrenergic receptor (β2-AR)/cAMP signaling pathway, resulting in a 2.7-fold increase in phosphofructokinase activity [99]. This process elevates lactic acid concentration to 8 mM, compared to 2 mM in control conditions, through monocarboxylate transporter 4 (MCT4) efflux, thereby acidifying the microenvironment and promoting the secretion of matrix metalloproteinases (MMPs) [100]. Epigenetic Transgenerational Memory: Stress-induced epigenetic modifications demonstrate long-term persistence. Chronic restraint stress elevates the methylation rate of the CDH1 (E-cadherin) promoter in gastric cancer cells from 12% to 68% [101]. MicroRNA Regulation: Stress reduces the expression of miR-200c/141 via glucocorticoid receptor (GR) signaling, decreasing it to 23% of levels observed in control groups, which alleviates the inhibition of ZEB1, leading to a 3.9-fold increase in protein levels [102]. Organoid experiments indicate that gastric cancer organoids pretreated with stress retain high metastatic potential for up to 14 days in a stress-free environment, suggesting the existence of epigenetic memory [103].

Interaction with H. pylori infection

Helicobacter pylori (H. pylori) infection is recognized as a significant risk factor for gastric cancer, with evidence suggesting a complex interplay between chronic stress and H. pylori infection that collaboratively facilitates gastric cancer metastasis. Research indicates that chronic stress can enhance the stress-activated expression of virulence factors associated with H. pylori. Specifically, neuro-microbial signaling mechanisms have been shown to remodel H. pylori pathogenicity; for instance, norepinephrine treatment has been found to upregulate the expression of the H. pylori CagA gene by 2.8-fold and to increase VacA secretion by 4.1-fold [76, 104]. These virulence factors compromise the integrity of the gastric mucosal barrier, trigger inflammatory responses, and induce cellular damage, thereby fostering an environment that is conducive to the initiation and progression of gastric cancer. Furthermore, stress-induced alterations in gastric acid pH (rising from 1.5 to 3.2) activate phosphorylation at the CagA Tyr972 site, which enhances its capacity to induce interleukin-8 (IL-8) secretion in epithelial cells, achieving concentrations of 1,235 pg/mL compared to 287 pg/mL in control groups [105]. A bidirectional vicious cycle is observed in which Helicobacter pylori infection exacerbates physiological stress responses. The CagA protein induces visceral pain hypersensitivity by activating TRPV1 channels and promoting the secretion of corticotropin-releasing hormone (CRH), which is increased by 2.3-fold [106]. Additionally, the VacA toxin impairs the mitochondrial function of regulatory T cells (Tregs), resulting in a 72% decrease in ATP production and leading to an imbalance in immune suppression [107]. Epidemiological studies indicate that individuals who are H. pylori-positive and exhibit high stress levels have a 6.2-fold increased risk of gastric cancer metastasis compared to those with only one of these risk factors (odds ratio = 6.2, 95% confidence interval 3.1–12.4) [108, 109].

Clinical evidence linking chronic stress to gastric cancer metastasis

Numerous large-scale cohort studies have demonstrated a significant correlation between psychological stress and the metastasis of gastric cancer. A multicenter cohort study conducted in China, involving 2,167 participants, indicated that gastric cancer patients with a preoperative Distress Thermometer score of 4 or higher exhibited a 1.8-fold increased incidence of liver metastasis three years post-surgery compared to those with a score below 4 (Hazard Ratio [HR] = 1.82, 95% Confidence Interval [CI] 1.34–2.47). Furthermore, a dose-response relationship was observed, whereby each 1-point increase in the Distress Thermometer score corresponded to a 21% escalation in metastasis risk [110]. This association persisted as statistically significant even after adjusting for confounding variables such as TNM staging and treatment modality (P = 0.003). Mechanistic investigations revealed that tumor tissues from patients experiencing high stress exhibited a 2.3-fold increase in the expression of β2-adrenergic receptors (ADRB2) compared to the control group. Elevated ADRB2 expression (Immunohistochemistry [IHC] score ≥ 3+) was directly linked to an increased risk of liver metastasis (HR = 2.31, 95% CI 1.56–3.41), implicating neural signaling as a pivotal factor in clinical metastasis [111]. The intricate relationship between stress-related hormonal profiles and metastasis markers provides novel insights for clinical monitoring. Specifically, the disruption of the circadian rhythm of serum cortisol is evident, as morning cortisol peak levels are 28% lower in gastric cancer patients with metastasis compared to those without, while nighttime trough levels are 1.9 times higher. This disruption correlates positively with circulating tumor cell (CTC) counts (r = 0.61, P < 0.001) [112]. Additionally, markers of the microbial-neural axis indicate that patients experiencing stress-related gut microbiota dysbiosis, such as a reduced Bacteroidetes/Firmicutes ratio, exhibit a 2.1-fold increase in CagA-positive H. pylori infection rates. These patients also face a 4.3-fold increased risk of liver metastasis (OR = 4.3, 95% CI 2.1–8.7) [113]. Furthermore, tumors may exert influence on central nervous system function by secreting specific factors, such as IL-6 and TNF-α, thereby establishing a “tumor → stress” feedback loop. Animal models reveal that the number of c-Fos-activated neurons in the paraventricular nucleus (PVN) of the hypothalamus increases by 3.2-fold in mice transplanted with gastric cancer cells, suggesting direct tumor regulation of the nervous system [114]. A clinical longitudinal study (n = 458) demonstrated that within six months following a gastric cancer diagnosis, patients exhibited an increase in stress scores, as measured by the Perceived Stress Scale (PSS-10), from a baseline of 12.3 ± 3.1 to 19.8 ± 4.5 (P < 0.001). However, the extent of this stress increase did not show a significant correlation with the risk of subsequent metastasis (P = 0.32), indicating that early changes in stress levels may primarily be influenced by the disease itself [115]. It is important to note the heterogeneity in stress measurement tools, as some studies utilized subjective questionnaires [116]. Furthermore, a nested case-control study utilizing the SEER database (n = 8,932) revealed that gastric cancer patients who encountered major negative life events, such as bereavement or unemployment, within five years prior to diagnosis experienced a 1.5-fold increase in the incidence of distant metastasis compared to the control group (OR = 1.52, 95% CI 1.23–1.88). This effect was more pronounced in individuals under 50 years of age (OR = 2.11) [117]. At the molecular level, RNA sequencing of tumor tissues from patients revealed a 2 to 3-fold upregulation of gene expression in neurodevelopmental pathways, such as Netrin signaling, indicating that stress may activate embryonic migration programs via epigenetic reprogramming [118]. In a prospective study, the European EPIC cohort (n = 12,543) employed a repeated measures design to assess stress exposure biennially. The findings indicated that individuals with a high cumulative stress load (score ≥ 75th percentile) over a 10-year period exhibited a 2.7-fold increased risk of gastric cancer metastasis compared to those with consistently low exposure (HR = 2.71, 95% CI 1.89–3.89) [119]. Notably, stress exposure in the 2–5 years preceding diagnosis had the most significant impact on metastasis risk (HR = 2.3), whereas stress management interventions post-diagnosis reduced the risk by 34% (HR = 0.66). A randomized controlled trial (NCT03047811) evaluated the effect of stress management on metastasis, revealing that participants in the Cognitive Behavioral Therapy (CBT) group experienced a 38% reduction in serum norepinephrine levels and a decrease in circulating tumor cell counts from a baseline of 8.2 ± 2.1 to 3.5 ± 1.3 per 7.5mL after six months of intervention (P = 0.004) [120]. In the biofeedback cohort, heart rate variability (HRV) training resulted in a 2.1-fold reduction in the expression of stress-related microRNA (miR-155) and was correlated with an extended progression-free survival, with a median PFS of 11.3 months compared to 8.7 months (P = 0.03) [121].

Potential intervention strategies

Pharmacological intervention

β-adrenergic receptor blockers exhibit considerable anti-metastatic potential through the inhibition of stress signal transduction pathways. Validation of propranolol’s mechanism: In a patient-derived xenograft (PDX) model of gastric cancer, administration of propranolol at a dosage of 10 mg/kg/day resulted in a reduction of lung metastases from 23 ± 6 in the control group to 7 ± 2, with statistical significance (P < 0.001). The mechanism of action of propranolol involves the inhibition of the ADRB2/cAMP/PKA signaling pathway and a 72% reduction in MMP-9 expression [15]. Clinical trial advancements: A phase II clinical trial (NCT04502082) demonstrated that propranolol, administered at 40 mg twice daily in combination with chemotherapy, extended the median progression-free survival (PFS) in patients with advanced breast cancer from 5.1 months to 8.3 months (hazard ratio = 0.61), and enhanced the clearance rate of circulating tumor cells (CTCs) by 2.4-fold [122]. The glucocorticoid receptor antagonist mifepristone has shown efficacy in counteracting stress-induced immunosuppression: Molecular mechanism: By inhibiting the physical interaction between the glucocorticoid receptor (GR) and STAT3, mifepristone reduces IL-6-induced PD-L1 expression from 1583 ± 234 mean fluorescence intensity (MFI) to 623 ± 89 MFI, as validated by flow cytometry [123]. Preclinical Evidence: In a chronic restraint stress mouse model, administration of mifepristone at a dosage of 50 mg/kg resulted in a 2.8-fold increase in CD8 + T cell infiltration density and achieved a 67% inhibition rate of liver metastasis [124]. Safety Challenges: A Phase I clinical trial (NCT05218732) is currently assessing the tolerability of low-dose mifepristone at 100 mg/day. Preliminary findings indicate an incidence of adrenal insufficiency of 12% (3 out of 25 participants) [125]. Synergistic Effects of Anti-inflammatory Drugs and Celecoxib’s Immunomodulatory Effects: In a stress model mouse study, celecoxib administered at 30 mg/kg increased the proportion of M1 macrophages from 18% to 43% and reduced serum IL-6 levels by 62% [126]. Combined Intervention Trial: A randomized controlled trial (RCT) involving 89 participants evaluated the combination of cognitive-behavioral therapy (CBT) with celecoxib at 200 mg twice daily. The results indicated that the 1-year metastasis-free survival rate in the combined treatment group was 68%, significantly higher than the 49% observed in the monotherapy group (P = 0.02) [120]. Cancer cell plasticity, characterized by the reversible transition between epithelial, mesenchymal, and stem-like phenotypes, constitutes a significant adaptive mechanism in response to chronic stress. Stress-induced signaling pathways, such as GR/STAT3 and ADRB2/PKA, may promote transient, drug-tolerant states that contribute to therapeutic resistance. As discussed in the review, “Unraveling the Dangerous Duet between Cancer Cell Plasticity and Drug Resistance [127]”, this phenotypic flexibility allows subsets of gastric cancer cells to evade targeted or immune therapies. This suggests that the combination of β-blockers with anti-EMT or epigenetic agents could potentially prevent plasticity-driven relapse.

Psychosocial intervention

Immune modulation through cognitive behavioral therapy (CBT): Structured psychological interventions have been demonstrated to enhance tumor immunity via multiple mechanisms. Enhanced T-cell function: A randomized controlled trial conducted at a single center (n = 56) revealed that an 8-week CBT intervention significantly increased the proportion of CD8 + T cells from 21.3 ± 4.1% at baseline to 25.7 ± 3.8% (P = 0.003), alongside a 1.9-fold augmentation in granzyme B secretion [120]. Neuroendocrine regulation: CBT was found to restore cortisol circadian rhythms, elevating the morning peak/nighttime trough ratio from 1.2 to 2.7, in comparison to 3.1 in healthy controls, which corresponded to a 53% reduction in circulating tumor cell (CTC) counts [128]. Molecular effects of mindfulness-based stress reduction (MBSR): MBSR has been shown to exert anti-metastatic effects through epigenetic modifications. In patients with gastric cancer who completed an 8-week MBSR program, there was an increase in FOXP3 promoter methylation rates in peripheral blood mononuclear cells (PBMCs) from 18% to 42%, as validated by pyrosequencing, leading to the inhibition of Treg function [129]. Additionally, serum miR-200c levels increased from 0.32 ± 0.08 to 0.67 ± 0.12 (relative expression), potentially reversing the epithelial-mesenchymal transition (EMT) process [130]. Establishing a Social Support Network: The relationship between social isolation and metastasis risk is well-documented. Epidemiological evidence, derived from an analysis of the SEER database, indicates that unmarried patients with gastric cancer exhibit a 1.7-fold increase in the 5-year distant metastasis rate compared to their married counterparts (34% vs. 20%). Furthermore, a one-point increment in social support scores correlates with a 14% decrease in mortality risk (Hazard Ratio = 0.86) [131]. Mechanistic investigations reveal that social support mitigates the activity of corticotropin-releasing hormone (CRH) neurons in the amygdala via the oxytocin system, thereby reducing stress hormone secretion by 41% [132].

Lifestyle adjustments

Optimization of Exercise and Dietary Interventions for Health Outcomes: A Scientific Approach The systematic optimization of exercise prescriptions reveals that regular physical activity can modulate the hypothalamic-pituitary-adrenal (HPA) axis, thereby exerting anti-metastatic effects. Specifically, an aerobic exercise regimen consisting of 150 min of moderate-intensity activity per week, such as brisk walking, has been shown to reduce the area under the salivary cortisol curve (AUC) by 28%, which correlates with a 37% decrease in circulating tumor cell (CTC) counts [133]. The distinct benefits of resistance training are also noteworthy; engaging in strength training twice weekly enhances natural killer (NK) cell cytotoxic activity by 1.6-fold, facilitated by the activation of interleukin-15 (IL-15) secretion from muscles, as measured by the 51Cr release assay [134]. In the realm of dietary interventions, precision design of anti-inflammatory diets demonstrates that specific nutrient combinations can produce synergistic effects. For instance, omega-3 fatty acid supplementation, with a daily intake of 2 g of EPA/DHA, significantly reduces serum interleukin-6 (IL-6) levels from 8.2 ± 1.5 pg/mL to 4.7 ± 0.9 pg/mL (P = 0.004) and downregulates vascular endothelial growth factor (VEGF) expression by 54% [135]. Additionally, the potentiation of polyphenols, such as curcumin (1 g/day) combined with quercetin (500 mg/day), has been shown to significantly lower the stress-related metabolite ratio of dog urine acid to tryptophan from 0.036 to 0.018 (P < 0.001) [136]. The regulation of circadian rhythms, phototherapy, and interventions in sleep schedules are critical for addressing stress-related rhythm disorders. A study demonstrated that morning bright light therapy, involving exposure to 10,000 lx of light for 30 min per day over a four-week period, resulted in a 2.1-hour advancement of the melatonin peak phase and a corresponding 2.3-fold increase in CTC clearance [137]. Additionally, implementing a time-restricted feeding strategy, which confines the daily eating window to 8 h (such as from 8:00 to 16:00), was found to reduce blood glucose fluctuations by 41% and inhibit the activity of the HIF-1α pathway [138].

Conclusion

Chronic stress significantly impacts the metastatic progression of gastric cancer through various mechanisms, including neuroendocrine pathways, immune suppression, and modifications within the tumor microenvironment. These mechanisms are interconnected and collectively enhance the invasive and metastatic potential of gastric cancer cells. Moreover, the combined effect of chronic stress and Helicobacter pylori infection further amplifies the risk of gastric cancer metastasis. Consequently, in the clinical management of gastric cancer, it is imperative to address not only the tumor itself but also the psychological well-being of patients. This approach aims to mitigate the detrimental effects of chronic stress, thereby improving treatment outcomes and enhancing patients’ quality of life. The future of oncology is poised to increasingly depend on precision medicine strategies that incorporate molecular profiling, immunomodulation, and psychoneuroendocrine regulation. By identifying stress-induced molecular signatures, such as the GR-STAT3 or ADRB2-HIF-1α pathways, clinicians may be able to stratify patients for combined therapeutic interventions, including the use of β-blockers, GR antagonists, or behavioral therapies. The integration of these strategies into personalized treatment frameworks has the potential to transform the management of metastatic gastric cancer.

Prospective

In this review, we explore the relationship between chronic stress and gastric cancer metastasis, as well as intervention strategies targeting chronic stress in gastric cancer metastasis, as shown in Figs. 1 and 2. In recent decades, significant advancements have been made in the understanding of carcinogenic mechanisms, which have been synthesized into the established hallmarks of cancer. Nevertheless, our comprehension of the molecular underpinnings of systemic manifestations and the fundamental causes of cancer-related mortality remains insufficient. It is imperative to elucidate the interactions between tumors and distant organs, as well as the complex environmental and physiological factors that influence both tumors and their hosts, to enhance the prevention and treatment of human cancers. Revolutionary breakthroughs in multi-omics technologies, encompassing molecular mapping and spatiotemporal dynamics, have facilitated spatial multi-omics analyses of stress signals within the tumor microenvironment. While traditional single-cell sequencing technologies can provide insights into cellular heterogeneity, they fall short in accurately pinpointing the dynamic transmission of stress signals within the tumor’s spatial niche. The latest advancements in spatial transcriptomics, such as the 10x Genomics Visium HD platform, when combined with mass cytometry (CyTOF) technology, enable comprehensive “neuro-immune-tumor” analyses at micrometer-level resolution within tissue sections. Construction of interaction maps, localization of stress signal hotspots, machine learning algorithms are employed to identify regions of high ADRB2 expression, commonly referred to as hotspots, which frequently coincide with zones of CD8 + T cell exclusion. When the spatial distance between these regions is less than 50 μm, the risk of metastasis is increased by a factor of 3.2 [139, 140]. Advancements in nerve fiber imaging-utilizing two-photon microscopy in conjunction with a Thy1-YFP transgenic mouse model, this study is the first to demonstrate enhanced contrast between MCF-10 A human breast epithelial cells and Thy1-YFP-cleared mouse brains [141]. This methodology holds potential for future application in visualizing stress-induced abnormal proliferation of sympathetic nerve fibers in gastric cancer liver metastases, as well as in elucidating the direct interactions between neural synapses and tumor stem cells (CD44+). The single-cell epigenomic analysis of stress memory indicates that stress-induced epigenetic modifications possess transgenerational inheritance capabilities. Utilizing single-cell ATAC-seq in conjunction with DNA methylation sequencing (scMethyl-seq) can provide insights into the molecular underpinnings of this memory, particularly through chromatin accessibility mapping. In mice subjected to chronic stress, the regions of open chromatin associated with epithelial-mesenchymal transition (EMT)-related genes, such as TWIST1, in gastric cancer cells were found to increase by 3–5 fold. Remarkably, this open chromatin state persisted for at least three generations of cell division, even in the absence of stress [142]. Intergenerational Intervention Window: Epigenetic editing tools, such as dCas9-DNMT3A, which target the closure of the SNAI1 gene promoter region [143] have demonstrated the potential to mitigate stress-induced metastatic capabilities [144], thereby offering novel insights for preventive interventions.Precision Targeting of the Neuro-Tumor Axis: The advancement of receptor isoform-specific pharmacological agents, from molecular design to intelligent regulation, is imperative. Current beta-blockers exhibit a lack of selectivity for adrenergic receptor subtypes (ADRB1/2/3), leading to cardiovascular side effects. The structural analysis of ADRB2 via cryo-electron microscopy (Cryo-EM) [145] is facilitating the development of a novel class of drugs, specifically allosteric modulators. Notably, the compound Cmpd-15 binds to the intracellular allosteric site of ADRB2, selectively inhibiting cAMP signaling without affecting baseline heart rate [146]. In the realm of bifunctional molecular design, ADRB2/GR dual-target PROTAC molecules [147], such as ARD-61, promote receptor protein degradation through ubiquitination, thereby significantly reducing the number of metastatic lesions in patient-derived xenograft (PDX) models without inducing adrenal insufficiency [148]. Furthermore, optogenetic regulation at neuroimmune interfaces offers precise spatiotemporal tools for intervention. For instance, vagus nerve activation therapy, achieved by expressing ChR2 at vagus nerve terminals in the gastrohepatic axis, utilizes 473 nm blue light stimulation to enhance NK cell infiltration, decrease IL-10 levels, and inhibit the formation of liver metastases [149]. Real-time Feedback System: An implantable fiber-optic device is utilized to monitor pH fluctuations within the tumor microenvironment. When the pH level falls below 6.8, indicative of heightened glycolytic activity, blue light is automatically activated to facilitate closed-loop regulation of stress-related metabolic abnormalities [150]. Precision Intervention in the Microbiome-brain-tumor axis: This encompasses approaches ranging from symbiotic regulation to synthetic biology, including the engineering of synthetic microbial communities, CRISPR-based gene circuit design, and the development of an intelligent probiotic system. Stress-sensing strains: engineered escherichia coli nissle 1917, equipped with a cAMP biosensor, initiates the expression of β-lactamase to degrade norepinephrine (NE) when intestinal NE levels exceed 200 nM, thereby reducing serum NE concentrations [151, 152]. Virulence factor neutralization is achieved through the competitive inhibition of Helicobacter pylori binding to gastric epithelial cells by Lactobacilli expressing CagA mimetic peptides, such as Lactobacillus reuteri DSM17938. This process has been shown to reduce VacA-induced apoptosis in preclinical models [153]. In the realm of phage therapy, CRISPR-Cas9 phages, such as ΦHP-3, offer precise targeting capabilities by selectively eliminating pathogenic H. pylori while preserving the commensal microbiota. This is facilitated by a dynamic regulatory system wherein phage-carried inducible promoters activate Cas9 expression at gastric acid pH levels below 3, leading to the cleavage of the CagA gene sequence and a subsequent reduction in the expression of H. pylori virulence factors [154]. Synergistic Effect of Stress Intervention: The combination of phage therapy and propranolol has been shown to decrease the incidence of gastric cancer liver metastasis in a dual-humanized mouse model characterized by H. pylori infection and chronic stress [155]. Digital Medicine and Artificial Intelligence: Transitioning from prediction to real-time intervention, a predictive model utilizing multimodal data fusion [156] incorporates data from wearable devices, liquid biopsies, and radiomics to develop a dynamic risk scoring system known as the Stress-Metastasis Index (SMI). This index is based on 12 parameters, including heart rate variability (HRV), serum cortisol slope, and circulating tumor cell (CTC) count, achieving an area under the curve (AUC) of 0.93 for predicting metastasis risk within three months [157]. Imaging Biomarkers: Deep learning algorithms are employed to analyze tumor edge texture features in CT images, enabling the identification of ADRB2 high-activity subpopulations, with sensitivity reaching [158]. Virtual Reality (VR)-driven behavioral intervention: The metaverse platform offers an immersive approach to stress management through Neurofeedback Training, which involves the real-time visualization of stress biomarkers, such as skin conductance, within VR environments. Patients are guided to regulate their breathing to transform the virtual setting from a “storm scene” to a “calm oasis.” Preliminary clinical studies have demonstrated a reduction in norepinephrine (NE) levels following an 8-week intervention [159]. In distributed clinical trials, blockchain technology is employed to ensure data security across multi-center VR intervention studies, with patients completing 80% of the intervention process remotely, thereby significantly enhancing enrollment efficiency [160]. The clinical translation framework has been redesigned to shift from an evidence-based to a practice-based, individualized stratified treatment system, which is based on precise matching of molecular subtypes and stress phenotypes. For the HER2-positive subgroup, the combination of an ADRB2 inhibitor with trastuzumab has shown promising results, with a phase II trial indicating an increase in the objective response rate (ORR) from 28% to 52% [161]. Epstein-Barr virus-associated gastric cancer: This study emphasizes the integration of programmed cell death protein 1 (PD-1) inhibitors with vagus nerve stimulation, given that stress signals exhibit a diminished immunosuppressive effect on this tumor type [162]. A multidisciplinary integrated diagnostic and therapeutic model has been proposed, establishing a collaborative “oncology-neuroscience-psychiatry” clinic. This model includes a standardized assessment process whereby patients, during their initial consultation, undergo concurrent psychological evaluation using the Perceived Stress Scale (PSS-10) [163], neuroimaging via functional magnetic resonance imaging (fMRI) to assess amygdala activity, and microbiome analysis through fecal metagenomics. An integrated report is generated within 72 h. Additionally, a dynamic monitoring network is implemented, utilizing implantable biosensors to continuously track cortisol and norepinephrine levels, with real-time data transmission to a cloud-based artificial intelligence platform to alert clinicians of potential metastasis risks [164]. The optimization of health economics models and cost-benefit analysis informs resource allocation, highlighting that stress management interventions cost $28,500 per quality-adjusted life year (QALY), which is significantly lower than the cost of targeted therapies ($150,000/QALY), and can effectively reduce hospitalization expenses [165]. Preventive screening strategies, such as annual combined stress-microbiome assessments for high-risk occupational groups (e.g., healthcare professionals), are projected to reduce future treatment expenditures significantly [166, 167]. Although existing literature offers compelling evidence of the association between chronic stress and the progression of gastric cancer, the majority of studies remain preclinical or correlative in nature. The variability in stress assessment tools and the scarcity of longitudinal data limit the ability to interpret causality. Future research should utilize standardized psychometric instruments and incorporate multi-omics profiling to elucidate patient-specific stress signatures. Furthermore, clinical trials that combine β-blockers or stress-reducing interventions with immunotherapy could provide essential translational validation.

Fig. 1.

The mechanism by which chronic stress promotes gastric cancer metastasis. Chronic stress activates the HPA and SNS axes, releasing cortisol and catecholamines, which bind to corresponding receptors on tumor cells. This triggers a signal cascade that drives EMT, angiogenesis, and immune suppression. HPA hypothalamic–pituitary–adrenal, SNS sympathetic-nervous-system, VEGF Vascular endothelial growth factor, EMT epithelial-mesenchymal transition

Fig. 2.

Intervention strategies targeting chronic stress in gastric cancer metastasis. MBSR mindfulness-based stress reduction, CBT cognitive behavioral therapy

Author contributions

Juntao Chen: Conceptualization, Investigation, Writing - Original Draft, Visualization.Yanling Zhang: Investigation, Writing - Original Draft, Formal Analysis.Tianyou Zhang: Investigation, Resources, Writing - Review & Editing.Zhipeng Wen: Methodology, Investigation, Data Curation.Yongfeng Li: Investigation, Writing - Review & Editing, Visualization.Yinzhuo Ye: Formal Analysis, Writing - Review & Editing.Guiqing Jia: Conceptualization, Supervision, Project Administration, Funding Acquisition, Writing - Review & Editing.Zili Zhou: Conceptualization, Supervision, Project Administration, Funding Acquisition, Writing - Review & Editing.

Data availability

All raw data and code are available upon request.The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.Requests for access to the raw data should be directed to Dr. Guiqing Jia (Email: jiaguiqing@med.uestc.edu.cn).

Declarations

Ethics approval and consent to participate

Not applicable. This article does not report any studies involving human participants or animals conducted by the authors.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.