Chronic psychological stress and gastric cancer: bidirectional associations, biological mechanisms, and clinical implications—a narrative review

Introduction

According to the Global Cancer Observatory and GLOBOCAN 2022 estimates, gastric cancer (GC) accounted for approximately 968,000 new cases and 660,000 deaths worldwide, ranking among the leading causes of cancer incidence and mortality and continuing to impose a substantial global health burden (1). Although advances in endoscopic screening, perioperative management, systemic therapy, and molecularly guided treatment have improved outcomes in selected patients, the overall burden of GC remains considerable, and its clinical course is influenced not only by tumor-related factors but also by patient-related and psychosocial conditions (1).

Among these factors, chronic psychological stress, particularly in the form of anxiety and depression, has attracted increasing attention because it is commonly observed in patients with GC and may adversely affect quality of life, symptom burden, treatment tolerance, and survival-related outcomes (2-5). Importantly, growing evidence suggests that the relationship between chronic psychological stress and GC may be bidirectional (4,6). On the one hand, the diagnosis of GC, together with nausea, vomiting, anorexia, weight loss, postoperative dysfunction, treatment-related adverse effects, and fear of recurrence, may precipitate or exacerbate anxiety and depressive symptoms (2,3). On the other hand, chronic psychological stress may also have potential biological links to GC progression through interacting neuroendocrine, inflammatory, immune, and microbiota-related processes, suggesting that in GC it may represent more than an accompanying emotional disturbance and may have broader implications for disease progression and clinical management (7-10).

Accordingly, a clearer GC-specific synthesis is needed to clarify the clinical significance of chronic psychological stress in GC and its potential biological links to disease progression. Although relevant studies have examined cancer-related anxiety and depression as well as aspects of GC biology, these lines of evidence have usually been considered separately rather than within a GC-centered synthesis integrating bidirectional clinical associations, biological links to tumor progression, and translational implications. This review synthesizes current evidence on the clinical significance of chronic psychological stress in GC, its potential biological mechanisms related to disease progression, and the implications of these findings for prognosis and patient management. By integrating psychological burden, biological mechanisms, and clinical implications, this review frames chronic psychological stress as a clinically relevant factor in GC rather than solely as a psychological comorbidity. We present this article in accordance with the Narrative Review reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0546/rc).

Methods

This narrative review was informed by targeted searches of PubMed, Web of Science, and relevant reference lists up to February 2026, using combinations of the following terms: “gastric cancer”, “chronic psychological stress”, “depression”, “anxiety”, “psychological distress”, “β2-adrenergic receptor”, “hypothalamic-pituitary-adrenal axis”, “inflammation”, “immune escape”, “microbiota”, “gut-brain axis”, and “supportive care”. Priority was given to GC-specific clinical, epidemiological, mechanistic, and interventional studies, while broader cancer-related or depression-related literature was cited only when it provided necessary biological or clinical context. As this article was designed as an integrative narrative review rather than a systematic review or meta-analysis, the selected literature was synthesized qualitatively to highlight clinical relevance, biological plausibility, and evidence gaps. The search strategy summary is provided in Table 1.

Clinical burden and epidemiological links between chronic psychological stress and GC

At the clinical level, the association between chronic psychological stress and GC is most clearly reflected in the substantial burden of anxiety, depression, and broader psychological distress observed after diagnosis. A meta-analysis estimated that depression affects approximately 37% of patients with GC, indicating that psychological morbidity is common rather than incidental in this population (2). Consistent with this, clinically significant anxiety or depression was identified in nearly one-third of patients with newly diagnosed advanced gastrointestinal cancer, and GC was among the malignancies more strongly associated with such symptoms (11). In elderly patients with GC, anxiety and depression were reported in 42.0% and 33.0% of cases, respectively, whereas in recurrent GC the corresponding prevalences were even higher, reaching 52.4% and 41.5%, respectively (12,13). Collectively, these findings indicate that psychological distress is common across multiple GC settings and may become more pronounced as disease burden accumulates.

Importantly, the clinical relevance of these disturbances extends beyond emotional symptom burden alone. In a cohort of 229 patients with GC, psychological distress was identified in 33.6% of patients and was associated with worse oncologic outcomes; in stage I–III disease it was linked to shorter disease-free survival, whereas in stage IV disease it was associated with poorer overall survival (14). Population-based data further support the clinical importance of this relationship. In a nationwide South Korean cohort, GC was associated with an increased risk of new-onset depression after diagnosis, with particularly elevated risks observed in women and in patients aged 60–69 years (4). Taken together, these studies suggest that psychological distress in GC should not be regarded simply as an expected emotional response to cancer, but rather as a clinically meaningful condition with implications for prognosis and care.

By contrast, evidence linking chronic psychological stress to GC susceptibility remains more limited and should be interpreted more cautiously. In a large population-based cohort from South Korea, psychiatric disorders were associated with a higher overall cancer incidence, and both anxiety disorder and major depressive disorder were independently linked to elevated cancer risk; however, these data were not GC-specific (15). More directly, a hospital-based case-control study reported that depression and stress were associated with increased odds of GC after multivariable adjustment (6). In addition, a longitudinal population-based cohort from Taiwan supported a broader bidirectional relationship between anxiety disorder and cancer overall, although it did not establish a GC-specific causal pathway (16). Therefore, current epidemiological data suggest that chronic psychological stress may be relevant not only to outcomes after GC diagnosis but also, more tentatively, to cancer vulnerability itself.

Potential biological mechanisms between chronic psychological stress and GC progression

Neuroendocrine initiation of the stress response: predominance of the sympathetic nervous system (SNS)/β2-adrenergic receptor (β2-AR) axis

Chronic psychological stress may influence GC progression initially through neuroendocrine dysregulation, particularly sustained activation of the SNS and, to a lesser extent, disturbance of the hypothalamic-pituitary-adrenal axis (HPA axis), thereby exposing tumor cells and the tumor microenvironment to persistent catecholamine- and glucocorticoid-related signals (17,18). However, the currently available GC-specific evidence indicates that this initiating layer is centered mainly on the SNS/β2-AR axis. In patients with gastric carcinoma, elevated catecholamine-related indices and sympathetic predominance were associated with poorer differentiation, deeper invasion, lymph node and distant metastasis, and inferior survival (19). Similarly, higher intratumoral sympathetic fiber density and increased β2-AR expression were associated with larger tumors, deeper invasion, more extensive nodal involvement, advanced stage, and less favorable survival (20). These observations support the clinical relevance of sympathetic activation in GC and suggest that stress-related adrenergic signaling is not merely a systemic accompaniment of malignancy, but may be linked to biologically aggressive disease behavior (19,20).

Experimental findings are consistent with this interpretation. Chronic restraint stress increased circulating catecholamines and cortisol while accelerating GC growth, invasion, and metastasis in vivo, and these effects were closely linked to β2-AR signaling rather than to a nonspecific stress response alone (18). More recent work further showed that GC tissues from patients with chronic stress exhibited higher β2-AR and PlexinA1 expression than tissues from patients without chronic stress, while chronic unpredictable mild stress enhanced tumor growth and increased the expression of β2-AR, PlexinA1, Ki-67, and epithelial-mesenchymal transition (EMT)-related markers in vivo (21). By comparison, evidence for the glucocorticoid-associated arm remains more limited but still suggestive. Peripheral blood cortisol and adrenocorticotropic hormone levels were higher in patients with stage III/IV GC than in those with stage I/II disease, and glucocorticoid exposure was linked to receptor tyrosine kinase-like orphan receptor 1 (ROR1)-associated malignant behavior in GC models (22). Taken together, current data support neuroendocrine dysregulation as an initiating layer through which chronic psychological stress may become biologically coupled to GC progression, with the strongest GC-specific evidence converging on sympathetic/β2-AR activation and glucocorticoid-related signaling best regarded as a contributory but less developed parallel component.

Immediate tumor-promoting consequences: invasion, EMT, plasticity, and early malignant transformation

Once this neuroendocrine initiating layer is engaged, the best-supported downstream consequences center on invasive reprogramming, EMT, tumor-cell plasticity, and adaptive survival. At the invasive front, catecholamine stimulation upregulates matrix metalloproteinase-7 (MMP-7) through β2-AR-dependent activation of activator protein-1 (AP-1)/c-Jun and signal transducer and activator of transcription 3 (STAT3) signaling, thereby linking stress-related adrenergic input to extracellular matrix degradation and enhanced invasive capacity (23). A major related consequence is EMT. Previous studies showed that β2-AR activation enhanced cluster of differentiation 44 (CD44)/STAT3 signaling (24), engaged the β2-AR-hypoxia-inducible factor-1α (HIF-1α)-Snail axis (25), and promoted extracellular signal-regulated kinase (ERK) phosphorylation (26), collectively driving EMT-associated molecular changes characterized by increased Snail and N-cadherin together with reduced E-cadherin. In addition, PlexinA1 was identified as an important downstream effector of β2-AR, and the β2-AR/PlexinA1 interaction further amplified EMT-associated reprogramming through Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling (27). Thus, the neuroendocrine initiating signals described above appear to be translated rather directly into a β2-AR-centered invasive and EMT program in GC cells.

This downstream program extends beyond invasion and EMT alone. Under chronic stress conditions, norepinephrine activated cAMP response element-binding protein (CREB) and subsequently the AMP-activated protein kinase/Unc-51 like autophagy activating kinase 1 (AMPK/ULK1) pathway, thereby increasing autophagic flux and supporting GC cell proliferation and survival (28). From another angle of phenotypic plasticity, depression-associated catecholamines induced a neuroendocrine-like phenotype through the β2-AR/c-Jun/metastasis-associated in colon cancer 1 (MACC1) axis, as reflected by synaptophysin upregulation, dense-core secretory vesicle formation, enhanced calcium signaling, and increased invasive and metastatic potential (29). Importantly, these consequences may not be restricted to progression of already established tumors. In a rat model, chronic restraint stress aggravated gastric epithelial malignant transformation through β2-AR-dependent Akt activation and p53 dysregulation, suggesting that adrenergic stress signaling may also participate in earlier carcinogenic events (30). Collectively, current evidence indicates that once chronic psychological stress is transduced through the neuroendocrine initiating layer, it converges first on direct tumor-cell programs characterized by enhanced invasion, EMT, adaptive survival, phenotypic plasticity, and facilitation of early malignant transformation in GC. Beyond these immediate consequences within tumor cells, stress-related signaling may be further amplified through oxidative, inflammatory, and immune-regulatory circuits, thereby stabilizing a tumor-promoting microenvironment.

Oxidative-inflammatory amplification, immune escape, and additional remodeling pathways

Beyond the immediate β2-AR-centered consequences described above, chronic psychological stress may further promote GC progression by amplifying oxidative stress, inflammatory signaling, and immunosuppressive remodeling. In patients with gastric adenocarcinoma and depression, reduced antioxidant capacity together with increased malondialdehyde and 8-hydroxy-deoxyguanosine indicated a marked oxidative imbalance in this clinical context (31). Consistent with this pattern, Huang et al. reported that GC patients with depression exhibited both elevated oxidative stress and dysregulated inflammation, while reactive oxygen species (ROS) activated ABL proto-oncogene 1 (ABL1) and downstream nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling in GC models (32). Pharmacologic inhibition of ABL1 attenuated these inflammatory signals, supporting a ROS/ABL1/NF-κB/STAT3 axis as one route through which stress-related oxidative imbalance may be translated into tumor-promoting inflammation (32).

This amplification may emerge even before overt carcinoma develops. In a gastric precancerous lesion model combined with chronic unpredictable mild stress, serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were increased, with TNF-α levels further elevated in the stressed group, while NF-κB, p53, and B-cell lymphoma 2 were upregulated and BCL2-associated X was reduced (33). These findings suggest that chronic stress may intensify inflammatory activation and disturb the balance between proliferation and apoptosis during premalignant gastric progression (33). Taken together, current evidence indicates that oxidative stress and inflammation in stress-related gastric tumorigenesis are not independent events, but rather mutually reinforcing effectors that can further sustain malignant progression.

Available evidence further indicates that this oxidative–inflammatory amplification is accompanied by progressive immune dysregulation. In a Helicobacter pylori-induced GC model, T helper 17 (Th17) cells were enriched during early gastritis and premalignant stages, whereas serum IL-6 and interleukin-10 (IL-10) increased and central memory CD4-positive and CD8-positive T cells decreased during GC transition (34). In elderly GC patients, higher Th17 cell and interleukin-17A levels were associated with anxiety and depression scores, suggesting that psychological burden in GC may coincide with a Th17-skewed inflammatory profile (13). At the effector level, FOLR2-positive tissue-resident tumor-associated macrophages were shown to inhibit CD8-positive T-cell function by co-expressing programmed death-ligand 1 (PD-L1) and IL-10, and combined blockade of programmed cell death protein 1 (PD-1) and IL-10 produced a stronger antitumor effect than either intervention alone in FOLR2-positive tumor-associated macrophage-high GC (35). In addition, β2-AR signaling has been shown in innate immune models to drive rapid IL-10 secretion and suppress pro-inflammatory cytokine release (36). Work in other tumor settings further suggests that IL-10 can dampen antitumor immunity at least partly through PD-L1 induction on myeloid cells, which provides mechanistic support for interpreting the GC findings (37). Overall, current evidence suggests that chronic psychological stress may amplify ROS-associated signaling, reinforce cytokine networks involving IL-6, TNF-α, IL-10, and Th17-related responses, and thereby foster an inflammatory yet immunosuppressive milieu permissive to immune escape in GC.

Beyond this oxidative-inflammatory and immune-regulatory amplification, chronic psychological stress may further stabilize GC progression through hormone-dependent and microbiota-linked metabolic remodeling. Recent evidence showed that depression accelerated GC growth with reduced estradiol levels and increased Notch receptor 3 (NOTCH3) expression, whereas estradiol supplementation counteracted this promotive effect, supporting a contributory role for the estrogen/NOTCH3 axis in stress-related tumor remodeling (38). A parallel process is evident at the microbiota-metabolite level, where chronic unpredictable mild stress disrupted gut microbial communities and fecal metabolic patterns, with a prominent decline in Blautia coccoides-derived 5Z-dodecenoic acid (5Z-D) (Figure 1) (39). Supplementation with B. coccoides or 5Z-D attenuated stress-associated glycolysis and malignant phenotypes in GC models, while 5Z-D directly inhibited RIOK2, thereby disrupting the RIOK2/BYSL axis that supports glycolytic activity and malignant progression (39). More broadly, microbiota-derived metabolites can enter host circulation and influence systemic metabolic homeostasis, which supports the biological plausibility of this remodeling layer (40). In addition, case-control data suggest that depression and stress may coexist with adverse dietary exposures, including higher salt and sugar intake and lower intake of potentially protective nutrients such as vitamin B6, implying that nutritional factors may modulate the endocrine-metabolic-microbiota axis rather than constitute an independent core mechanism (6).

Figure 1 Schematic summary of the proposed mechanism by which 5Z-D attenuates chronic psychological stress-associated gastric cancer progression. CUMS induces gut microbiota dysbiosis, accompanied by a decreased abundance of Blautia coccoides and reduced 5Z-D levels. 5Z-D supplementation directly binds to and inhibits RIOK2 and disrupts the RIOK2/BYSL axis, leading to reduced glycolysis and malignant phenotypes in GC cells. The downstream antitumor effects include decreased lactate production, reduced expression of Ki-67 and PCNA, and inhibition of GC cell proliferation, migration, and invasion. 5Z-D, 5Z-dodecenoic acid; CUMS, chronic unpredictable mild stress; GC, gastric cancer; PCNA, proliferating cell nuclear antigen; RIOK2, RIO kinase 2.

Taken together, these mechanisms are better understood as an interconnected, self-reinforcing circuit than as isolated pathways (Figure 2). The neuroendocrine, tumor-promoting, oxidative-inflammatory, immune, and microbiota-metabolic layers converge on a limited set of shared effectors. Adrenergic β2-AR signaling and ROS-driven ABL1 activity both feed into a common STAT3/NF-κB program that governs invasion, EMT, and inflammatory amplification (23,24,27,32). In parallel, β2-AR-induced IL-10 aligns sympathetic tone with the IL-10/PD-L1-associated immunosuppression of GC (35-37). Oxidative stress, immune evasion, and adrenergic signaling therefore reinforce one another rather than acting independently.

Figure 2 Proposed closed-loop molecular network linking chronic psychological stress and gastric cancer. In the forward (stress-to-tumor) direction, neuroendocrine activation dominated by the sympathetic nervous system/β2-adrenergic receptor axis and the hypothalamic-pituitary-adrenal/glucocorticoid axis engages four interconnected mechanism modules—tumor-cell programs, oxidative-inflammatory signaling, immune escape, and microbiota-metabolic alterations—that converge on a shared set of molecular nodes (STAT3, NF-κB, IL-10/PD-L1) to drive gastric cancer progression. Tumor-derived IL-6 and TNF-α feed back onto the hypothalamic-pituitary-adrenal axis (feed-forward amplification). In the reverse (tumor-to-stress) direction, increased tumor burden, systemic inflammation, and microbiota disruption act along the microbiota-gut-brain axis to sustain anxiety and depression, closing the bidirectional loop. Solid arrows denote forward (navy) and reverse (teal) signaling; double-headed grey arrows denote pathway cross-talk/convergence; the dashed arrow denotes feed-forward amplification. 5Z-D, 5Z-dodecenoic acid; ABL1, ABL proto-oncogene 1; EMT, epithelial-mesenchymal transition; HPA, hypothalamic-pituitary-adrenal; IL-10, interleukin-10; IL-6, interleukin-6; NF-κB, nuclear factor kappa B; NOTCH3, Notch receptor 3; PD-L1, programmed death-ligand 1; ROS, reactive oxygen species; SNS, sympathetic nervous system; STAT3, signal transducer and activator of transcription 3; TAM, tumor-associated macrophage; Th17, T helper 17; TNF-α, tumor necrosis factor-α; β2-AR, β2-adrenergic receptor.

This circuit is also self-reinforcing and bidirectional. Tumor-derived IL-6 and TNF-α can activate the HPA axis, regenerating the neuroendocrine signals that initiate the cascade (41). Stress-related dysbiosis and the decline of protective metabolites such as 5Z-D further couple the circuit to the microbiota-gut-brain axis (8,39,42). This axis is the same conduit that links the forward cascade to the reverse, tumor-to-stress direction examined below, thereby closing the loop. Because these mechanisms converge on shared nodes, single-target interventions may be insufficient. This consideration has nonetheless drawn growing therapeutic interest to nodes such as β-adrenergic signaling, IL-10/PD-L1, the estrogen/NOTCH3 axis, and microbiota-derived metabolites.

How GC aggravates anxiety and depression

Persistent clinical burden across the disease course

In surgical GC patients, postoperative anxiety and depression worsened progressively over time, with Hospital Anxiety and Depression Scale-Anxiety (HADS-A) and Hospital Anxiety and Depression Scale-Depression (HADS-D) scores increasing from baseline to 36 months after discharge, while baseline depression was associated with poorer disease-free and overall survival (3). Likewise, a nationwide cohort study from South Korea showed that GC was associated with a higher risk of new-onset depression, with particularly elevated risks observed in women, patients aged 60–69 years, and those with a prior history of depression (4). In recurrent GC, anxiety and depression were more frequent than in newly diagnosed GC and healthy controls, and shorter time to recurrence was independently associated with both outcomes (12). Taken together, these findings support the view that GC itself can function as a sustained stressor, especially when patients face repeated treatment, ongoing symptom burden, and fear of recurrence. This burden is not static but tends to track disease events, intensifying around treatment transitions and recurrence, and it is often accompanied by reduced quality of life and poorer treatment adherence (3,12).

Tumor-driven inflammation and central neuroimmune signaling

This reverse association is unlikely to reflect psychosocial stress alone. Studies of cancer-related depression have shown that chronic inflammation, stress-response activation, and gut microbiota dysbiosis are recurrent biological contributors (9). A growing body of research indicates that the tumor-derived inflammatory milieu driving GC progression also acts on the central nervous system. Pro-inflammatory cytokines produced within the gastric tumor microenvironment, particularly IL-6 and TNF-α, can reach the brain through humoral routes, including transport across the blood–brain barrier, and through vagal afferent signaling (43). Within the brain, these signals promote microglial activation and neuroinflammation, which preclinical cancer models have linked to depressive- and anxiety-like behavior. Surgical resection of the tumor partially reverses this tumor-induced neuroinflammation, suggesting that the tumor itself, and not only psychological factors, contributes to these changes (44).

In depression research, pro-inflammatory cytokines have been shown to activate the hypothalamic-pituitary-adrenal axis and to contribute to affective and cognitive symptoms, while higher cortisol levels are associated with poorer cognitive performance (41,45). This inflammatory and neuroendocrine activity also provides a biological basis for the symptom clustering often seen in GC, in which depressed mood co-occurs with fatigue, anorexia, and sleep disturbance as part of a cytokine-associated sickness-behavior phenotype (43).

Neurotransmitter and microbiota-gut-brain pathways

Central inflammation also reshapes neurotransmitter metabolism. Cytokine-driven induction of indoleamine-2,3-dioxygenase diverts tryptophan away from serotonin synthesis and toward neuroactive kynurenine-pathway metabolites. This shift has been proposed as a shared biological link between cancer and depression (46), and it is consistent with inflammation-depression models and with the kynurenine-pathway alterations reported in GC (41,47). Cytokine signaling can also disturb the norepinephrine and dopamine systems that help regulate mood (43). Anorexia and cachexia, which are common in GC, may contribute through the same cytokines: area postrema neurons can sense circulating IL-6 and relay this signal through a brainstem-to-basal ganglia circuit that suppresses mesolimbic dopamine, producing apathy- and depression-like motivational deficits; blockade of IL-6 reversed these deficits, supporting a causal contribution of this cytokine (48). Nutritional impairment may further limit the availability of monoamine precursors.

This framework is particularly relevant to gastrointestinal malignancy, where the microbiota-gut-brain axis has been proposed as a central link between gastrointestinal cancer and depression, involving dysbiosis, altered microbial metabolites, and disruption of intestinal and blood-brain barrier homeostasis (8). In GC specifically, gut microbiota and microbial metabolites are increasingly recognized as regulators of immune homeostasis, inflammation, and the tumor microenvironment (42). Extending this to affective outcomes, a recent study that included patients with stomach cancer reported altered plasma microbiota-gut-brain metabolites, including glucocorticoids, short-chain fatty acids, and tryptophan-derived metabolites, that co-varied with depression and anxiety symptom clusters (49). Consistent with this concept, Helicobacter pylori-associated atrophic gastritis has been associated with psychological distress and depressed mood, suggesting that persistent gastric pathology may exert psychobiological effects even before overt malignancy develops (50). Because this microbiota-gut-brain route also participates in the forward, stress-to-tumor direction, the two directions are better understood as a continuous process than as separate phenomena. The GC-specific evidence for several of these steps remains less developed than that for the forward direction. Nonetheless, the available data support a model in which GC-related anxiety and depression may arise not only from the emotional impact of cancer, but also from sustained inflammatory and stress-related disturbances along the gut-brain axis.

Clinical implications

These observations have clinical implications. Because anxiety and depression in GC may be persistent, prognostically relevant, and partly reinforced by ongoing biological disturbance, psychological assessment should not be limited to the time of diagnosis. Instead, it should continue, using validated instruments, throughout postoperative follow-up, adjuvant treatment, and recurrence (3,4). Monitoring should be intensified for patients who may be more vulnerable to emotional deterioration, including women, older patients, those with recurrent disease, and those with a prior history of depression (4,12). In GC, therefore, anxiety and depression should be regarded not as incidental emotional symptoms, but as clinically meaningful conditions that warrant active surveillance and timely supportive intervention throughout care.

Clinical and therapeutic implications: from treatment efficacy to integrated supportive care

Impact of chronic psychological stress on treatment efficacy

Beyond influencing tumor biology and mood, chronic psychological stress and the distress accompanying a cancer diagnosis may also affect how patients respond to anticancer treatment. In advanced GC, psychological distress has been identified as a factor independently associated with reduced efficacy of palliative chemotherapy, alongside its negative effects on quality of life and cancer-related fatigue (5). This influence may operate through both behavioral and biological routes. Behaviorally, depression and anxiety are well-established risk factors for reduced adherence to medical treatment, with depressed patients showing markedly lower adherence across conditions (51), which in oncology can translate into missed doses, dose reductions, and incomplete treatment.

The most direct biological evidence has emerged in the setting of immunotherapy. In a prospective cohort of patients with advanced GC treated with anti-PD-1 immune checkpoint inhibitors, baseline emotional distress was independently associated with poorer tumor response and prognosis, including a lower disease control rate and higher risks of progression and death, an association that persisted after propensity-score matching (52). A further prospective cohort in advanced gastroesophageal cancer found that baseline emotional distress, together with elevated peripheral inflammatory markers, predicted worse checkpoint-inhibitor outcomes, pointing to a synergistic psycho-inflammatory effect (53). The same pattern extends beyond gastrointestinal tumors: in the prospective STRESS-LUNG-1 study in advanced non-small-cell lung cancer, pretreatment emotional distress predicted worse efficacy of first-line checkpoint-inhibitor therapy, and higher baseline serum cortisol was likewise associated with shorter progression-free survival, leading the authors to propose emotional distress as a potential “psycho-biomarker” of immunotherapy response (54).

These associations are consistent with the stress-related pathways already described. The same β2-AR and glucocorticoid signaling that promotes tumor progression has, in preclinical models, been shown to impair the efficacy of anti-PD-1 blockade—an effect reversible by β-adrenergic antagonism—and to reduce tumor responsiveness to chemotherapy (55,56). Sustained psychological stress could therefore blunt treatment efficacy through the very mechanisms that drive GC progression. As current clinical data remain observational and require prospective confirmation, recognizing and managing chronic stress may be relevant not only to quality of life but also to treatment outcomes.

Established supportive interventions with direct clinical relevance

Given the bidirectional relationship between chronic psychological stress and GC, therapeutic management should not focus solely on tumor control but should also address coexisting or treatment-emergent anxiety and depressive symptoms. At present, the interventions with the most direct clinical relevance are symptom-directed pharmacotherapy, structured psychotherapeutic intervention, and nutritional-behavioral supportive care integrated into routine oncology management. Their current value lies not in directly reversing every mechanism discussed above, but in reducing emotional burden, supporting treatment adherence, and preserving quality of life during cancer care (57).

Current evidence in people with cancer, pooled in a Cochrane review, suggests that antidepressants may reduce depressive symptoms compared with placebo at 6–12 weeks, although the certainty of evidence remains very low and no clear superiority has been established among commonly used drug classes (58). Therefore, in GC, antidepressants may be considered for clinically significant depression, particularly when symptoms are persistent, functionally impairing, or likely to compromise oncologic treatment, but selection is currently better guided by individual symptom profile, tolerability, comorbidity, and general psycho-oncology practice than by robust GC-specific comparative evidence (58).

Structured psychotherapeutic interventions currently have the strongest direct relevance for emotional symptom management in GC. Pooled evidence in gastrointestinal cancer indicates that cognitive-behavioral therapy, reminiscence therapy, and narrative nursing can reduce anxiety and/or depression compared with conventional care (59).

GC-focused studies, so far limited to small individual trials, further suggest that virtual reminiscence therapy during chemotherapy, reminiscence therapy-based care in recurrent disease, and cognitive behavioral stress management in unresectable advanced GC may alleviate psychological burden and improve quality of life (60-62). Collectively, these approaches appear to represent practical and relatively low-burden non-pharmacological options for distressed GC patients.

Supportive care in GC should also incorporate nutritional and behavioral components rather than treating mood symptoms in isolation. In a single controlled trial, advanced GC patients undergoing chemotherapy who received personalized nutrition combined with acceptance and commitment therapy showed improved psychological resilience, reduced chemotherapy-related adverse effects, and enhanced quality of life compared with routine management alone (63). Accordingly, established supportive interventions in GC are best viewed not as isolated psychiatric add-ons, but as interventions that address emotional symptoms, nutritional status, and treatment tolerance together.

Potential adjunctive strategies and integrated care perspectives

In addition to these symptom-directed interventions, other strategies aim to act more directly on the biological pathways linking chronic psychological stress and GC, although most remain at the preclinical or early translational stage. As outlined in earlier sections, several biologically relevant pathways—including β2-adrenergic stress signaling, glucocorticoid/ROR1-associated tumor-promoting effects, ROS/ABL1/NF-κB/STAT3-related inflammatory signaling, IL-10/PD-L1-associated immune suppression, IL-6 signaling implicated in cancer-related affective symptoms, and gut microbiota-related modulation—have emerged as potential therapeutic targets in GC, although evidence for therapeutic modulation remains largely preclinical or early translational (22,29,32,35,39,48).

Among these early translational signals, microbiota-related intervention is of particular interest because it may connect emotional symptoms with neuroendocrine status, intestinal flora, nutritional recovery, and overall well-being. In patients with depression after radical surgery for GC, a non-randomized controlled study found that Bifidobacterium triple viable bacteria-assisted mirtazapine was associated with greater improvement in depressive symptoms and several neuroendocrine, microbial, nutritional, and quality-of-life measures than mirtazapine alone (64). Although these findings remain preliminary, they are notable because they align closely with the microbiota-, metabolic-, and neuroendocrine framework discussed in earlier sections.

Accordingly, the main value of this mechanistic framework at present lies less in redefining treatment algorithms than in supporting a more integrated model of care. In GC, symptom-directed pharmacotherapy, structured psychotherapy, nutritional support, and selected adjunctive approaches should be considered within a multidisciplinary framework according to disease stage, symptom burden, and patient tolerance (57). Thus, the translational implication of this framework is not that every mechanistic node is already clinically targetable, but that GC care may increasingly move toward layered, biologically informed, and integrated supportive management.

To synthesize the heterogeneous evidence base across the proposed bidirectional framework, Table 2 summarizes the major domains linking chronic psychological stress with GC, including clinical burden, epidemiological associations, biological links, reverse effects of GC on anxiety and depression, and therapeutic implications. This evidence map highlights that the current evidence is relatively consistent for psychological burden after GC diagnosis and comparatively well developed for sympathetic/β2-adrenergic signaling, whereas susceptibility-related epidemiological evidence, immune remodeling, microbiota-linked mechanisms, and pathway-directed interventions remain less mature.

These differences in evidence maturity also define the major limitations of the current field and indicate where future research should be prioritized.

Limitations and future directions

Although accumulating evidence supports a clinically meaningful but still uneven bidirectional relationship between chronic psychological stress and GC, the current literature remains insufficient to establish a fully integrated mechanistic framework or an immediately translatable clinical model. At the epidemiological and clinical level, the available evidence should be interpreted with caution because substantial heterogeneity persists across studies with respect to study design, population characteristics, psychiatric assessment methods, and clinical context (65). In addition, much of the currently available population-based evidence has been generated in East Asian settings, including retrospective cohort data from Taiwan, which may limit the generalizability of current conclusions to broader populations (16). Larger prospective, multicenter, and multiethnic studies are therefore needed to clarify the strength, directionality, and generalizability of this association.

At the mechanistic level, the available evidence suggests a multi-layered but still incomplete framework involving neuroendocrine dysregulation, oxidative-inflammatory amplification and immune escape, and hormonal, metabolic, and microbiota-related remodeling. Among these components, the GC-specific evidence is currently more developed for neuroendocrine and downstream tumor-promoting signaling, whereas other layers of the proposed network remain less extensively characterized. Moreover, these processes have largely been characterized in parallel rather than within a unified systems framework, and their temporal relationships, hierarchical organization, and subtype-specific relevance in GC remain insufficiently defined. In addition, although this review has discussed both the stress-to-tumor direction and the reverse effect of GC on anxiety- and depression-related outcomes, the biological links underlying this reciprocal interaction remain unevenly supported across different pathways. Current mechanistic models should therefore be regarded as biologically plausible but still incomplete. Future studies should move beyond single-axis interpretation and incorporate single-cell sequencing, spatial transcriptomics, and longitudinal multi-omics approaches to better resolve the dynamic stress–tumor interaction network.

Microbiota-related mechanisms represent a promising but still insufficiently defined component of this field. Although available studies support a potential role for microbiota-gut-brain signaling in the reciprocal interaction between affective disturbance and gastrointestinal malignancy, the current GC-specific evidence remains fragmented and largely preliminary (8,9). Functionally relevant microbial taxa, metabolite signatures, candidate strains, and reproducible GC-specific microbial patterns have not yet been clearly established, and optimal intervention strategies also remain uncertain. Accordingly, microbiota-oriented interventions should still be regarded as exploratory, and their mechanistic specificity, patient selection, and translational feasibility require validation in rigorously designed GC studies.

From a translational and clinical-management perspective, one of the major challenges is the persistent gap between mechanistic rationale and high-quality clinical evidence. At present, antidepressants, structured psychotherapeutic interventions, and integrated nutritional-behavioral supportive care have the most direct clinical relevance, whereas most adjunctive or pathway-directed strategies remain preliminary (57-59,63). Current intervention evidence is strongest for symptom-directed pharmacotherapy and structured psychological support, while pathway-directed strategies related to β-adrenergic stress signaling, glucocorticoid-associated effects, inflammatory signaling, immune suppression, and microbiota-related modulation are still supported mainly by preclinical or early translational studies. It therefore remains unclear which patients are most likely to benefit, how different interventions should be combined, and whether multidimensional treatment models can simultaneously improve psychological outcomes and conventional oncologic endpoints. In addition, the implementation of integrated care in routine practice continues to face practical barriers, including time constraints, inefficient referral pathways, uneven access to psycho-oncology services, and the absence of standardized multidisciplinary workflows. Future progress will therefore depend not only on identifying effective interventions, but also on developing feasible delivery models that can be embedded into real-world oncology practice. In this context, multidisciplinary collaborative care, biomarker-guided stratification, telehealth-supported psychosocial management, and pragmatic evaluation of integrated supportive-care pathways combining pharmacologic, psychotherapeutic, nutritional, and behavioral components warrant further investigation.

Conclusions

Taken together, current evidence supports a clinically meaningful but still evolving bidirectional association between chronic psychological stress and GC. At the epidemiological and clinical level, anxiety, depression, and broader psychological distress are common in patients with GC and are associated with less favorable outcomes, while stress-related psychiatric conditions may also be linked, more tentatively, to increased GC susceptibility. At the biological level, chronic psychological stress may contribute to GC progression through multiple interconnected and biologically plausible pathways, whereas GC itself may aggravate anxiety and depression through sustained disease burden together with biologically embedded host responses. Clinically, these findings indicate that psychological status is relevant across several connected dimensions of GC care. For risk awareness, the tentative association with susceptibility suggests that incorporating brief depression and anxiety screening into the follow-up of higher-risk groups, such as individuals with chronic atrophic gastritis or a family history of GC, may identify a potentially modifiable factor, although current evidence does not establish stress reduction as a proven preventive strategy. For prognostic evaluation, because distress is associated with poorer quality of life, treatment adherence, treatment efficacy, and survival, baseline psychological status may help stratify patients at diagnosis and before major treatment decisions, complementing conventional prognostic assessment. For individualized care, validated assessments can be repeated at key transitions, including surgery, adjuvant therapy, and recurrence. Closer monitoring is warranted for more vulnerable patients, such as women, older individuals, and those with prior depression. For service organization, these considerations support a multidisciplinary model in which a positive oncology-based screen triggers a defined referral pathway to psycho-oncological and nutritional care rather than ad hoc management.

Although many aspects of this interaction remain incompletely defined, the available evidence supports the view that, in GC, chronic psychological stress is relevant not only to emotional well-being, but also potentially to disease progression, treatment tolerance, and supportive care needs across the disease course. Future progress will require prospective epidemiological studies, more integrated mechanistic investigation, and rigorously designed multidisciplinary intervention trials to determine whether more integrated, stress-informed management strategies can ultimately improve both psychological well-being and oncologic outcomes in patients with GC.

Acknowledgments

Figures 1,2 and the Graphical Abstract were created in BioRender. nus, Y. (2026) https://BioRender.com/4px3tmm.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0546/rc

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0546/coif). The authors have no conflicts of interest to declare.

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