Chronic stress: a fourth etiology in tumorigenesis?

Abstract

Chronic stress, driven by persistent psychological, environmental, or physiological factors, is a prolonged heightened state of stress response that disrupts homeostasis. When unmanaged, it will lead to sustained negative emotions such as depression, loneliness, anxiety, and emotional adversity. This persistent emotional distress not only exacerbates mental health disorders but also poses significant risks to physical health. Increasing evidence suggests a strong link between chronic stress, stress-related hormones, and the rising incidence of malignancies. As a result, chronic stress might be recognized as a potential “fourth etiology” of cancer, alongside physical, chemical, and biological carcinogens. As a potential etiological driver of tumorigenesis, chronic stress-related hormones such as glucocorticoids and catecholamines or neurotransmitters have been implicated in various aspects of tumor initiation, promotion, and progression. Additionally, chronic stress influences tumorigenesis through multiple mechanisms, including tumor microenvironment remodeling, microbial dysbiosis, drug resistance promotion, as well as the regulation of oncogenic signaling pathways. Hence, mitigating the impact of chronic stress could be an effective method of cancer prevention and therapy. However, it remains a significant challenge in the assessment of chronic stress as a cancer etiology. Moreover, the link between stress-associated obesity and cancer offers novel insights into underlying mechanistic pathways in cancer research. Repurposing preventive and therapeutic approaches targeting stress-related tumorigenesis may provide deeper insights into the interplay between chronic stress and cancer, ultimately improving patient outcomes and quality of life.

Introduction

The etiology of cancer is highly complex and multifactorial, it is attributed to a complex interaction between various modifiable and non-modifiable factors, such as chemical, physical, and biological carcinogens. As insights into cancer etiology deepen, increasing attention has turned to the impact of psychological stress on tumor development. Psychological stress is typically classified into two forms: acute and chronic stress. Acute stress, which endures for minutes to hours, activates the body’s adaptive “fight or flight” responses. In contrast, chronic stress arises from sustained exposure to stressors over weeks, months or even years, resulting in persistent and maladaptive physiological activation [1]. Acute stress provokes a rapid surge in stress-hormone levels that subsides quickly once the stressor is removed. However, when such stressors recur or persist over time, their cumulative impact can emulate the physiological and pathological consequences of chronic stress [2, 3]. Therefore, we mainly discuss chronic stress as a potential etiology in tumorigenesis. Chronic stress associated stressful life events, including heavy work pressure, financial difficulties, interpersonal conflicts, academic stress, communication barriers, physical illness, and stress-related obesity contribute to both physiological and psychological disorders [4, 5]. In addition to the intangible pressures and influences from daily life and work, the regulation of stress-related physiological hormones also plays a significant role in chronic stress-related diseases.

Chronic stress increases stress-related hormones by continuously activating the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) [6]. Upon activation, the SNS releases catecholamines, including norepinephrine and epinephrine, through sympathetic nerve fibers and the adrenal medulla, while the HPA axis stimulates the release of glucocorticoids from the adrenal cortex [7]. Beta-adrenergic receptors (β-ARs), as the main effector of SNS, are involved in a variety of cellular processes, including the modulation of heart rate, blood pressure, and immune function. In the context of chronic stress and cancer, β-AR signaling has been implicated in the progression of tumor growth and metastasis, as it can enhance angiogenesis, promote cell survival, and facilitate the epithelial-to-mesenchymal transition (EMT), key processes involved in cancer malignancy driven by activation of the AKT-p53, and the plexinA1 pathway via β2-ARs [8–10]. Meanwhile, HPA axis is an important part of the neuroendocrine system, involved in controlling responses to stress and regulating many physical activities. When induced by HPA axis, glucocorticoids participate in metabolic and immune regulation [11]. Anatomically, both the SNS and HPA axis are involved in many physiological processes, and their disorders lead to the occurrence of various diseases, including cancer [12, 13]. In cancer, external stimuli and internal physiological changes also sustain chronic stress, leading to the activation of HPA axis and SNS [14–17]. Chronic stress–associated negative emotions, such as depression and anxiety are particularly prevalent in lung cancer [18, 19]. However, in other cancers, including breast, head and neck, liver, lymphoid, and hematopoietic malignancies, negative emotions are also associated with poor survival outcomes [20]. Another observational study demonstrates an association between work-related stress and an increased risk of lung, colorectal, and esophageal cancers [21]. Prolonged exposure to social isolation has been shown to promote the genetic expression of glycolysis and lipid synthesis [22, 23]. The other category of chronic stress includes physiological stressors such as surgical stress, chemotherapy stress, and radiotherapy stress, which can alter the tumor microenvironment (TME) and immune system, thereby promoting resistance to cancer treatments [19, 24–26] (Fig. 1). Hence, the chronic exposure to these stressors triggers negative emotions, ultimately increasing the risk of cancer incidence and mortality in patients [27, 28]. To thoroughly investigate the functions and mechanisms of chronic stress in preclinical studies, different kinds of stressors have been tried to mimic chronic stress in research, including chronic restraint stress (CRS) and chronic unpredictable stress (CUS). These paradigms have consistently shown that chronic stress accelerates tumor malignancy in vivo, confirming its promotive role in tumorigenesis.

Fig. 1.

Chronic stress as the potential fourth etiology in tumorigenesis. With physical, chemical and biological carcinogens, chronic stress might be recognized as the fourth etiology of tumorigenesis. Various physiological and psychological chronic stressors elicit mental stress, contributing to cancer initiation, promotion, progression, and metastasis via multifaceted biological pathways. This figure was created by Biorender (https://app.biorender.com/)

Here, we propose that chronic stress may be attributed as the fourth cancer etiology which has a significant impact on tumorigenesis. Moreover, we delineate the potential mechanisms by which chronic stress and stress-related hormones drive cancer initiation, promotion and progression. Ultimately, this work aims to deepen our understanding of how chronic stress drives tumorigenesis, intending to inform the new insight into cancer etiology and provide more effective intervention strategies. To address these challenges, further research is required to unravel the comprehensive molecular mechanisms through which the neuroendocrine system contributes to carcinogenesis under chronic stress.

Chronic stress as a potential contributor to human cancer etiology

Emerging perspectives on cancer etiology

Cancer etiology is typically categorized into three major types: physical, chemical, and biological carcinogens. Each category plays a distinct role in the development and progression of cancer. Physical carcinogens include ionizing radiation (IR), ultraviolet (UV) radiation, and other forms of physical agents that cause DNA damage, ultimately contributing to cancer development [29–32]. Chemical carcinogens are substances that can cause cancer through direct chemical interaction with DNA or by promoting cancer through other biochemical pathways. Examples include tobacco, asbestos, aflatoxins, and various industrial chemicals such as benzene and certain pesticides [33–36]. Biological carcinogens encompass microorganisms, viruses, and parasites. Notable examples include the human papillomavirus (HPV), which is linked to cervical cancer [37]; the Epstein-Barr virus (EBV), which is associated with nasopharyngeal carcinoma and lymphomas [38, 39]; and the Helicobacter pylori (H. pylori) infection, which is linked to gastric cancer [40]. These biological factors can lead to cancer by inducing chronic inflammation, altering immune responses, or directly modifying host cell DNA. However, these carcinogenic factors are all exogenous, the role of the host itself in the occurrence and development of cancer has long been overlooked. For humanity itself, general risk factors for cancer include poor nutrition and unhealthy lifestyle. However, adopting a balanced natural diet and a healthy lifestyle may only serve as a complementary or alternative approach to cancer treatment [41]. While the chronic stressor/stress in humans predominantly disrupt biological characteristics supporting inflammation-immune context to support cancer development [42]. With modern life accelerating and work pressures mounting, chronic psychological stress and related coping behaviors, including tobacco use, excessive alcohol consumption and stress-induced obesity, are increasingly recognized as significant contributors to cancer development. According to US Surgeon General reports, tobacco is the leading preventable cause of cancer, followed by obesity and alcohol. Alcohol consumption alone increases the risk of seven cancer types and accounts for ~ 20,000 deaths per year in the United States [43]. In 2025, an estimated 124,730 lung cancer deaths will occur in the US, ~ 85% (~ 106,150) attributable to cigarette smoking, with the remainder due to secondhand smoke (~ 3,500) and other combustible tobacco products (~ 15,100) [44]. These behavioral risk factors including tobacco use and alcohol intake not only drive carcinogenesis but also induce chronic psychological stress by disrupting brain chemistry [45]. Besides, chronic stress activates the HPA and SNS, promoting cravings for “comfort foods” and obesity [46]. Obesity drives cancer development by promoting metabolic and inflammatory disruptions, which significantly increases the risk of cancer [47]. In summary, chronic stress, as a major contributor to psychological changes, is increasingly recognized as the fourth critical factor in cancer etiology, significantly contributing to the initiation, promotion and progression of cancer, as well as other chronic diseases (Fig. 1).

Chronic stress as a potential etiological driver of tumorigenesis

A growing body of research has clearly shown that there is a close link between chronic stress and tumorigenesis by establishing mouse models that mimic stress-related or stress hormone-related tumorigenesis by using major depression methods, such as chronic social defeat, social instability, learned helplessness, food or water deprivation, and others [48–52] (Fig. 2). A gastric tumorigenesis mouse model was successfully established through the combined usage of H. pylori infection and chronic stress treatment [52]. Restrain, food deprivation, water deprivation, isolation, and forced swimming were adopted randomly in this mouse model to mimic a kind of unpredictable chronic mild stress. These findings illustrate the tumor-promoting effect of chronic stress in H. pylori–induced gastric tumorigenesis. Under stress conditions, alpha 1d-adrenergic receptors (α1d-AR) binds SerpinA1 and leads to its ubiquitination in the presence of norepinephrine. Meanwhile, β2-AR accelerates the progression from gastritis to tumorigenesis in H. pylori–infected mice under stress by decreasing CD8+ T cells and increasing interleukin (IL)-1α. Furthermore, both α- and β-blockers effectively prevented gastric tumorigenesis induced by the combination of chronic stress and H. pylori infection [52]. The involvement of the ubiquitination system was also revealed in CRS model of liver carcinoma, where epinephrine stabilizes pleomorphic adenoma gene like-2 (PLAGL2) through the upregulation of ubiquitin-specific protease 10 (USP10) involved in tumorigenesis [53]. Besides, chronic stress has been shown to promote esophageal squamous cell carcinoma (ESCC) tumorigenesis in combination with 4-nitroquinoline 1-oxide (4-NQO) [54]. Chronic stress–induced elevation of cortisol levels significantly enhanced ESCC cell proliferation and cell-derived xenograft (CDX) tumor growth. Moreover, a psychological stress-cortisol-high mobility group box (HMGB)-2-low density lipoprotein receptor (LDLR) axis has been identified as the key mechanism promoting ESCC under chronic stress conditions. Notably, both this pathway and elevated cortisol concentrations are predictive of neoadjuvant therapy efficacy in ESCC patients in clinical settings [54].

Fig. 2.

Chronic stress promotes tumorigenesis in various cancer types. Different chronic stressors were randomly and unpredictably administered to mice for long-term exposure, ultimately inducing mental stress in the mouse models. Frequently used chronic stressors include restraint, food deprivation, water deprivation, failed courtship, cage tilting, forced swimming, tail suspension, social defeat, and others. Chronic stress significantly promotes CDX and/or orthotopic tumor growth in breast, esophageal, colorectal, liver, lung, gastric, head and neck, and IR-induced (lymphomas and sarcomas) tumorigenesis. This figure was created by Biorender (https://app.biorender.com/)

In a breast cancer xenograft mouse model, chronically stressed mice exhibited more aggressive tumor growth and enhanced cancer stem cell (CSC) self-renewal [55]. Furthermore, chronic stress-induced epinephrine markedly promotes the stem-like properties of breast cancer cells by activating lactate dehydrogenase A chain (LDHA)-dependent metabolic rewiring and lactate production. This process, in turn, mediates MYC stabilization and SLUG transcription, driving stem-like phenotypes. Notably, vitamin C has been identified as an LDHA-lowering agent that can help combat chronic stress–associated breast cancer [55]. In addition, psychological stress induced by a CRS model was found to promote breast cancer stem-like phenotypes and tumorigenesis by elevating proline synthesis and activating the cyclic guanosine 3’,5’-cyclic monophosphate (cGMP)-protein kinase G (PKG) signaling pathway. These findings further suggest that alleviating chronic stress could serve as a potential therapeutic strategy for breast cancer patients experiencing psychological stress [56]. Besides, social defeat negatively affects cancer therapeutic outcomes and immunosurveillance in both urethane-induced non-small-cell lung cancer (NSCLC) and the azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colorectal carcinoma orthotopic mouse models. Stress-induced upregulation of glucocorticoids (in serum) and Tsc22d3 (in tumor-infiltrating dendritic cells [TIDCs]) subverts immunosurveillance. These results highlight that intercepting glucocorticoid-induced Tsc22d3-mediated immunosuppression is a promising approach to improve outcomes in mental stress–associated tumorigenesis [57]. Moreover, in lung tumorigenesis, norepinephrine stimulates the phosphorylation of L-type voltage-dependent calcium channels (VDCC) through the β2-AR mediated PKA pathway in CUS mouse model, calcium mobilization triggered exocytosis of insulin like growth factor 2 (IGF2) [58]. In addition, CRS elevates glucocorticoids to decrease p53 function and promotes IR-induced tumorigenesis in p53^+/− mice, predominantly lymphomas and sarcomas [59]. Collectively, these mouse model studies provide strong evidence that chronic stress plays a significant role in promoting tumorigenesis etiologically.

Stress hormones contribute to tumorigenesis: initiation, promotion and progression

Beyond compelling evidence from animal models, mechanistic data and clinical relevance support our hypothesis that chronic stress contributes to all stages of tumorigenesis—initiation, promotion, and progression. The significance of the dynamic neuroendocrine system driving via chronic mental stress in cancer pathophysiology can lead to profound alterations in critical biological pathways, contributing to the onset and progression of cancer [7, 60–62]. The HPA and SNS systems actively participate in tumorigenesis mediated by chronic stress [63–65]. The activation of AR [52, 66–70] and glucocorticoid receptors (GR) [71, 72] is necessary to regulate tumorigenesis. The synthesis of neuronal progenitors, stem cells, and mesenchymal-type cells represents a loss of lineage characteristics, leading to the adaptions of neural cells that support tumorigenesis through the release of norepinephrine and other catecholamines [58, 73]. Circulating stress hormones, including catecholamines and glucocorticoids, play crucial roles in modulating tumorigenesis by impacting tumor biology and the surrounding microenvironments [74]. The sustained surge of glucocorticoids and catecholamines within the TME promotes tumorigenesis. Peripheral nerves control TME and promote distinct mechanisms of angiogenesis, invasion, and metastasis [75]. Moreover, the crosstalk between nerve and tumor facilitates the most established hallmarks of cancer [76, 77]. Hence, tumorigenesis is ostensibly supported by chronic stress, providing a malignant environment across various types of cancer at different levels.

Stress hormones and tumorigenesis: initiation

Due to the mutagenic nature of cancer, observing stress-induced DNA damage in tumors is difficult; most evidence comes from controlled cell line studies. However, Gidron et al. compile findings linking psychological stress to DNA damage in both animal and human research [78, 79]. Stress hormones including epinephrine, norepinephrine and cortisol have been shown to induce DNA damage, impair DNA repair mechanisms, and disrupt cell cycle transcriptional regulation in murine 3T3 cells [80]. Furthermore, Falcinelli et al. demonstrated the oncogenic effects of chronic stress hormones on DNA damage and repair [81], reinforcing their role in tumor initiation. It is reported that stress responses through β2-AR cause DNA damage via Gs-PKA, and arrestin beta 1 (ARRB1). Morevoer, chronic activation of the β2-AR by isoproterenol, adrenaline, or noradrenaline, whether in mice or cultured U2OS cells, resulted in reduced p53 levels and accumulated DNA damage. Mechanistically, isoproterenol triggered murine double minute 2 (MDM2) activation through a beta-arrestin-dependent phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, leading to phosphorylation of MDM2 and subsequent p53 degradation [82], declaring the critical step of tumor initiation. The observed DNA damage accumulation was attributed to impaired DNA repair mechanisms. Emerging evidence further supports that stress hormones can suppress p53 function via MDM2 activation, highlighting a critical link between adrenergic signaling and genomic instability [83]. Glucocorticoids (e.g., hydrocortisone, dexamethasone) repress breast cancer gene 1 (BRCA1) promoter activity and downregulate its expression in non-malignant mammary cells. This repression is sustained only with continuous glucocorticoid exposure; however, its phenomenon is absence in malignant cell lines. It is suggested that elevated glucocorticoids may thus initiate breast cancer by reducing BRCA1-dependent DNA repair in normal epithelium. Conversely, unliganded glucocorticoid receptor upregulates BRCA1 promoter activity [84, 85], hence there is a need of more evidence to reveal the clearer mechanism of initiation process in the presence of stress hormones, particularly glucocorticoids. Moreover, in the aspects of epigenetics, the GR activation drives DNA methylation at CpG sites and modifies histone methylation/acetylation, reshaping chromatin accessibility. These epigenetic alterations are complemented by GR-mediated microRNA regulation, for example, upregulation of miR-708 [86] and downregulation of miR-346/493 accelerate cell cycle progression by upregulating cyclin D1 in breast cancer [62].

Stress hormones and tumorigenesis: promotion

In addition to initiation, evidence indicates that stress hormone–mediated activation of oncogenic signaling pathways can induce aberrant proliferative responses in cancer cells. Catecholamines (norepinephrine and epinephrine), which are involved in response to physical or emotional stress, have emerged as key mediators linking chronic stress to cancer promotion [87]. Chronic stress significantly promotes catecholamine, enhancing tumorigenesis in vivo, while activating transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein 1 (AP-1), cAMP response element-binding protein 1 (CREB), and signal transducer and activator of transcription (STAT)-3, along with ERK-janus kinase (JNK)- mitogen-activated protein kinase (MAPK) signaling in vitro [88]. Researchers noted that norepinephrine activity in glioma cells depends on the β-AR and responsible for the further activation of PI3K-AKT signaling pathway under CRS conditions and promotes the proliferation of glioma cells [89]. When activated by norepinephrine, cyclic AMP-dependent transcription factor (ATF1) enhances cancer stemness by simultaneously transactivating nuclear pluripotency factors (MYC and NANOG) and mitochondrial biogenesis regulators nuclear respiratory factor 1 (NRF1) and transcription factor A, driving both nuclear reprogramming and mitochondrial rejuvenation. This reveals that cancer cells acquire stem-like properties through a norepinephrine-ATF1 orchestrated nucleus-mitochondria collaborative program [90]. Besides, norepinephrine exacerbates advanced high-grade serous carcinoma (HGSC) progression through colony-stimulating factor 2 mediated anoikis resistance [91]. Meanwhile, norepinephrine-CREB1-miR373 axis promotes colon cancer [92]. In oral carcinoma, CRS dramatically promoted cancer development through the inhibition of aldehyde dehydrogenase 3 (ALDH3A1) expression by norepinephrine and influence on mitochondrial metabolism [93]. This stress-induced epinephrine disrupts metabolic pathways, with a particular emphasis on the β2-AR-PKA-CREB1 pathway, which enhances the expression of glycolytic enzymes including glucose transporter 1 (GLUT1), hexokinase 2 (HK2), and phosphofructokinase, platelet (PFKP). As a result, the increased glycolysis supplies the essential energy required for the accelerated growth and survival of cancer cells [94]. Furthermore, CUS conditions are marked by elevated serum norepinephrine levels and increased tyrosine hydroxylase (TH) expression in the bone marrow [95]. CUS elevates serum norepinephrine and corticosterone levels, while optogenetic activation of TH terminals in the ventral tegmental area (VTA)-medial prefrontal cortex (mPFC) can alleviate these stress effects [96]. CUS/CRS model intensifies the advancement of glioblastoma and increases the levels of dopamine receptor D2 (DRD2) stimulating the activation of extracellular signal-regulated kinase (ERK)-1/2. This activation, in turn, suppresses the activity of glycogen synthase kinase 3β (GSK-3β), leading to the activation of β-catenin. Meanwhile, ERK1/2 activation increases the expression of TH, which leads to an increase in dopamine release and the formation of an autocrine positive feedback loop [51]. Likewise, In CRS, β2-AR-ERK1/2 pathway recognized to be activated by chronic stress and contributes to the proliferation and metastasis of triple negative breast cancer (TNBC) [97].

Chronic stress also accelerates the promotion of hepatocellular carcinoma (HCC) by modulating the function of secreted frizzled-related protein 1 (sFRP1) [98]. In addition of norepinephrine, the action of epinephrine is also mediated via α1, α2, and β-ARs that through definite pathways [99]. It is reported that stress-induced epinephrine promotes the development and stemness of colorectal cancer through the CCAAT enhancer-binding protein beta (CEBPB)-tripartite motif (TRIM2)-p53 axis [100]. Therefore, more efforts should be carried out to finalize the mechanism of epinephrine in tumorigenesis. In addition, emerging evidence addressing the significance of glucocorticoids in ESCC tumorigenesis in vitro and in vivo [54]. Chronic stress markedly elevates cortisol levels, which in turn enhances tumorigenicity by transcriptionally upregulating the endoplasmic reticulum stress by glucose-regulated protein 78 (GRP78) [101], and activating the TEA domain transcription factor 4 (TEAD4) [102] to promote CSC maintenance. Meanwhile, recent evidence suggests that glucocorticoids induced-β-hydroxysteroid dehydrogenase type 1 (HSD1) is associated with the immunosuppressive response [103].

Stress hormones and tumorigenesis: progression and metastasis

Chronic stress increases cancer progression through mechanisms involving neurotransmitters and stress hormone signaling, as well as by influencing the TME, modulating immune function, promoting drug resistance and disrupting microbial homeostasis. These processes collectively contribute to inflammation, metastasis, immune suppression, angiogenesis and/or drug resistance, further exacerbating cancer progression (Fig. 3; Table 1).

Fig. 3.

The underlying mechanism of chronic stress in accelerating cancer malignancy. Chronic stress promotes cancer malignancy through stress-related hormones. Glucocorticoids, epinephrine, norepinephrine and dopamine via sympathetic while acetylcholine and serotonin via parasympathetic generate a supportive tumor microenvironment, modulate microbial dysbiosis, and promote drug resistance, contributing to cancer invasive progression. This figure was created by Biorender (https://app.biorender.com/)

Table 1.

Murine models of chronic stress in promoting tumorigenesis

Model	Animal Model	Animal Type	Mechanism	Effect	Drugs	References
Glioma
CUS and CRS	Orthotopic	BALB/c-nu and C57BL/6J mice	DRD2/ERK/β-catenin axis and Dopamine/ERK/TH positive feedback loop	Metastasis	DRD2 antagonist + DNA-methylating drug	[51]
Lymphoma
CRS	Orthotopic	BALB/c-nu mice	Tumor cell dissemination via β-AR/VEGFC	Metastasis	β-AR antagonist	[137]
CRS	Orthotopic	SCID mice	Tumor cell dissemination via β1,3-AR signaling	Metastasis	β-AR antagonist	[138]
Breast Cancer
CUS	Orthotopic	BALB/c mice	MDSC accumulation via β2-AR and IL6/STAT3 pathway	Metastasis	β-AR antagonist / IL6 blocking/ JAK2 and STAT3 inhibitor	[95]
CRS	CDX	Nu/Nu mice, C57BL/6J	Metabolic rewiring via β2-AR/LDHA/Myc/SLUG	Stem-cell-like traits	β-AR antagonist; Vitamin C reduces LDHA	[55]
CRS	Orthotopic	BALB/c mice	Neutrophil accumulation via β2-AR/SP1 in TDEs	Pre-Metastatic Niche	β-AR antagonist	[152]
CRS	Orthotopic	BALB/c mice	Gut dysbiosis/LRP5/β-catenin	Cancer Stemness	Butyric acid/High Fat Diet	[179]
Lung Cancer
CRS	CDX	Nu/Nu mice	β2-AR signaling by an LKB1/CREB/IL-6-	Drug Resistance	β-AR antagonist + TKIs to abrogate EGFR inhibitor	[195]
CRS	CDX	C57BL/6	β2-AR/cAMP/PKA/CREB	Stem-cell-like traits + Drug Resistance	Atypical Antipsychotic	[204]
CUS	CDX	C57BL/6	5-HT and Kynurenine pathway	Metastasis	Antipsychotic (SSRI)	[120]
CUS	CDX	FVB	β2-AR/PKA/VDCC	Metastasis	β-AR antagonist	[58]
CRS	CDX	BALB/c mice	HIF1A-AS3/M2-like macrophage polarization	Pre-Metastatic Niche	HIF1α-Inhibitor	[127]
Liver Cancer
CRS	CDX	C57BL/6 mice	β2-AR/c-Myc/PLAGL2/USP10	Metastasis	β-AR antagonist	[53]
CRS	CDX	C57BL/6 mice	Myeloid accumulation via β2-AR and CXCR2	Metastasis	β-AR antagonist	[115, 117]
CRS	CDX	BALB/c mice	T cell exhaustion via β-AR/PD-L1	Metastasis	β-AR antagonist	[150]
CRS	CDX	C57BL/6 mice	Monocytes and Macrophage accumulation via β-AR signaling	Metastasis	β-AR antagonist	[135]
Pancreatic Cancer
CRS	Orthotopic	BALB/c-Foxn1nu nude athymic mice	Tumor cell dissemination via β2-AR signaling	Metastasis	β-AR antagonist	[136]
Gastric Cancer
CRS	In-situ	BALB/c-nu mice	β2-AR/ERK1/2-JNK-MAPK	Metastasis	β-AR antagonist	[88]
CUS	Orthotopic	BALB/c-nu mice	β2-AR/PlexinA1	Metastasis	β-AR antagonist	[9]
CUS	CDX	BALB/c and ADRβ2 KO mice	β2-AR/IL-1α and α1d-AR/SerpinA1 complex	Metastasis	α, β-AR antagonist	[52]
Colorectal Cancer
CRS	CDX	C57BL/6	β2-AR/PKA/CREB1	Metastasis	Glycolysis inhibitor/ β2-AR antagonist	[94]
CRS	CDX	BALB/c-nu mice	β2-AR/TGF-β1 signaling/HIF-1α/VEGF	Angiogenesis	Human monoclonal VEGF-A neutralizing antibody, β-AR antagonist	[128]
CRS	CDX	BALB/c-nu mice	β2-AR/cAMP/PKA/VEGF	Angiogenesis	TKIs + β-AR antagonist	[196]
Ovarian Cancer
CRS	Orthotopic	Nude mice	β2-AR/cAMP/PKA/VEGF	Angiogenesis	β-AR antagonist	[133]
CRS	CDX	Nude mice	Modulate norepinephrine/AKT/β-catenin/SLUG axis	Metastasis	Melatonin	[162]

CUS: Chronic unpredictable stress, CRS: Chronic restrain stress, CDX: Cell derived xenograft, α-AR: Alpha adrenergic receptor, β-AR: Beta-adrenergic receptor, DRD2: Dopamine receptor D2, TDE: Tumor derived exosomes, SSRI: Selective serotonin reuptake inhibitor

Tumor microenvironment (TME)

Both locally produced (released within the TME) and systemically controlled (via the brain–immune axis) catecholamines and glucocorticoids modulate immune cell composition and function. These effects include, increase regulatory T cells (Tregs), reduction in T helper (Th) cells [104, 105], suppression of natural killer (NK) cells [62, 106, 107], elevation of myeloid-derived suppressor cells (MDSCs) [71, 108], and tumor-associated macrophages (TAMs) mobilization [72, 109, 110]. Chronic stress contributes to TME via the binding of stress neurotransmitters/hormones to receptors on tumor and stromal cells. Chronic stress impairs the ability of immune system to recognize and eliminate cancer cells [111]. It also suppresses immune responses and may even promote immune tolerance [112]. Consequently, these immunosuppressive conditions are accompanied by the upregulation of different pro-inflammatory cytokines [107, 110, 113–121]. Glucocorticoids, epinephrine, and norepinephrine reduce the activity of granulocytes and mononuclear cells, finally compromising immune function [122]. Moreover, the TME exhibits increased levels of pro-inflammatory cytokines, including IL-6, IL-1β, and tumor necrosis factor-α (TNF-α), which sustain the bidirectional relationship between psychological distress and cancer progression [123, 124]. In ovarian cancer who are experiencing protracted stress, Src kinase is activated by norepinephrine stimulation, which is essential for IL-6 expression [125].Enhanced adrenergic signaling by chronic stress stimulates tumor cells to secrete chemokine (C-C motif) ligand (CCL)-2, which in turn promotes the recruitment and infiltration of CD14+/CD68+ macrophages into the TME thereby contributing to tumor-associated immune modulation and cancer progression [126]. Chronic psychological stress accelerates lung cancer progression by upregulating the lncRNA hypoxia-inducible factor (HIF)1 A-antisense RNA 3 (AS3), which forms a positive feedback loop with HIF-1α to drive tumor growth and metastasis. HIF1A-AS3 translationally activates HIF-1α via Y box binding protein 1 (YBX1), while HIF-1α reciprocally enhances HIF1A-AS3 transcription. This axis promotes M2-like macrophage polarization, fostering a pro-tumorigenic microenvironment [127]. It also reported that norepinephrine in CRS mouse models was able to induce the expression of HIF-1α via transforming growth factor‑β1 (TGF-β1) signaling, resulting in an increase in vascular endothelial growth factor (VEGF) secretion and tumor angiogenesis [128]. The activation of adrenergic receptors stimulates VEGF and matrix metalloproteinases (MMP) secretion to promote angiogenesis in human cancers [129–133]. Moreover, low-density lipoprotein receptor-related protein 1 (LRP1)-signal regulatory protein α (SIRPα) axis imbalance the result of GR signaling in TAMs, which inhibits the phagocytosis of tumor cells by macrophages [134]. Moreover, it promotes HCC proliferation via norepinephrine and the leptin receptor (LEPR) by disrupting TAM polarization through β-adrenergic signaling [135]. CRS via β-ARs triggered tumor cell dissemination [136], it has been proven that CRS reshapes the lymphatic network depending on cyclooxygenase 2 (COX2) inflammation mediated by macrophages through β-ARs signaling to initiate the progression of prostaglandin E2 (PGE2) and VEGFC, while PGE2 amplifies inflammation by increasing vascular permeability, promoting immune cell infiltration, and sustaining a tumor-favorable microenvironment [137, 138]. In addition, chronic stress enhances the secretion of chemokine (C-X-C) motif ligand (CXCL)-2 and CXCL3, which in turn upregulates the expression of chemokine receptor (CXCR2)-2 in myeloid cells [115]. This promotes the recruitment and infiltration of myeloid cells into the TME, contributing to tumor progression and immune modulation [15]. Catecholamines recruit MDSCs, which are distinguished by a CD11b+Gr1+ phenotype in the bone marrow to increase the ratio of adenosine triphosphate (ATP)/mitochondrial reactive oxygen species (mROS) [108, 139]. Recent findings have also uncovered a novel link between chronic stress and anti-tumor immunity, highlighting the role of MDSCs as an indirect consequence of reward system activation in the VTA [140].

β-AR modulates the antitumor immune response and apoptosis by promoting the expansion of MDSCs while simultaneously reducing CD8+ and CD4+ T cells, as well as NK cells. This process is also associated with increased expression of programmed cell death protein-1 (PD-1) [62, 141]. However, epinephrine is also shown to decrease tumor burden by activating NK cell mobilization and redistribution [142, 143]. This further impairs dendritic cell antigen presentation, resulting in the failure to initiate CD8+ T cells activation and interferon-γ (IFN-γ) secretion, ultimately reducing PD-1 expression [144, 145]. Furthermore, chronic stress via glucocorticoids/ norepinephrine reduces the number of CD8+ T cells and cytotoxic T lymphocytes while impairing dendritic cell antigen presentation, contributing to T cell exhaustion [104, 146–149]. Chronic stress via adrenergic hormones also inactivates the STAT1-interferon regulatory factor (IRF)-1 pathway, leading to the simultaneous suppression of major histocompatibility complex (MHC)-I and upregulate the programmed cell death ligand-1 (PD-L1) expressions reducing T cell surveillance [150]. Moreover, chronic stress promotes metastasis by inhibiting T-cell infiltration and increasing neutrophil infiltration via the action of glucocorticoids, creating a microenvironment conducive to metastatic cell colonization [151]. Besides, chronic stress via glucocorticoids and adrenaline has been reported to increase the population of Tregs and MDSCs, both of which suppress anti-tumor immune responses [105, 108, 110, 117]. CRS causing adrenergic stimulation significantly increased the secretion of tumor-derived exosomes, which were subsequently internalized by pulmonary neutrophils. This internalization enhanced neutrophil recruitment through an autocrine CXCL2 signaling loop and ultimately activated the toll-like receptor 4 (TLR4)-NF-κB pathway, thereby exacerbating metastasis [152]. Moreover, Additionally, in both CRS and CUS models, acetylcholine also accelerates CXCL2 expression, which leads to NETosis and further promotes metastasis [153]. For instance, stress-induced neutrophils can produce neutrophil extracellular traps (NETs) triggered by glucocorticoid and supporting metastasis, while metastatic burden via chronic stress can be prevented by digesting NETs with DNase I [50].

Chronic stress activates key oncogenic signaling pathways, such as the JNK-STAT and p38 pathways, which play essential roles in promoting cancer cell proliferation and tumor progression, underscoring its critical influence on the TME [154–156]. Additionally, chronic stress activates both β1- and β2-ARs due to increased norepinephrine and epinephrine levels, triggering downstream STAT3 and Src signaling. This promotes oncogenic processes such as proliferation, apoptosis resistance, migration, invasion, and EMT. These pathways drive extracellular matrix (ECM) remodeling and pre-metastatic niche formation, supported by cancer-associated fibroblasts (CAFs), facilitating metastasis across various cancer types [72, 141, 157–159]. Furthermore, continuous exposure of glucocorticoids is efficient for proliferation and migration of fibroblast [160]. Norepinephrine and epinephrine in TME closely linked to EMT, characterized by the downregulation of E-cadherin and upregulation of N-cadherin, SNAIL, and SLUG [55, 161]. In epithelial ovarian cancer (EOC), CRS increases EMT markers such as TWIST, SLUG, SNAIL, and β-catenin to facilitate abdominal implantation metastasis. Moreover, β-catenin co-expressed with SLUG and norepinephrine in tumor tissues after stress treatment to further promote EOC migration and invasion [162]. In addition, norepinephrine induces the secretion of brain-derived-neurotrophic factor (BDNF), and nerve growth factor (NGF) and MMP, thereby enhancing TME innervation and sustaining adrenergic signaling [163]. Glucocorticoid levels also assure inflammation discouraging immunity to increase the vulnerability of cancer [164]. The supporting mechanism continues with the epigenetic changes including acetylation, histone methylation and regulation of micro RNAs or metabolic reprogramming which directly inhibits the anti-tumor function of tumor infiltrating lymphocytes (TILs) and NK cells, thereby promoting tumor progression by reshaping immune cells [81, 165, 166]. Chronic stress via glucocorticoids also promotes the expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1), which helps in metastatic colonization process [167]. Additionally, chronic stress stimulates the central nervous system (CNS) regulating the synthesis of other neurotransmitters such as 5-HT (5-hydroxytryptamine/serotonin) via serotonergic neurons, acetylcholine cholinergic neurons mediate parasympathetic responses and maintain the signaling between tumor and immune cells [168, 169]. These neuroendocrine alterations create an imbalance between protective and suppressive immune responses, fostering an immunosuppressive TME that accelerates tumor progression [170]. Overall, these findings indicate that chronic stress profoundly alters the TME, disrupting anti-tumor immunity and promoting cancer malignancy. Further research is needed to explore how integrating stress management strategies to ameliorate negative mental stress in anti-cancer therapy.

Microbial dysbiosis

Psychological stress also contributes to cancer progression via microbial dysbiosis [171, 172]. It was also revealed that depressive inclinations have increased in breast cancer patients linked with gut microbiota. It was reported that microbial dysbiosis characterized by increased abundance of Alcaligenaceae (family) and Sutterella (genus) was associated with higher distress levels, whereas higher levels of Streptococcaceae (family) and Streptococcus (genus) were linked to lower distress [173]. Moreover, genera Pseudomonas, Akkermansia were decreased, while Ruminococcus, Allistipes were increased in breast cancer patients [174]. Chronic stress disrupts biological functions and alters gut microbiota, further compromising the body’s defense mechanisms and weakening the immune response [111, 175]. Stress-induced alterations in the gut microbiota exacerbate negative effects on the CNS, driving tumor proliferation, migration and angiogenesis. For example, the microbiota generates various signaling molecules—including quorum-sensing molecules (QSM), bacterial components, microbial metabolites, neurotransmitters (5-HT, GABA), and neuropeptides that influence intestinal epithelial cells, enterochromaffin cells, or traverse the intestinal barrier to modulate immune cells (e.g., T cells, dendritic cells) within the lamina propria. These microbial-derived signals, along with activated immune cells, can enter systemic circulation and subsequently migrate to the brain [176, 177]. The descending pathways through which stress modulates microbial communities, a pivotal component of gut-brain crosstalk, are not yet fully characterized. In continuation, gut microbiota disrupts the level of neurotransmitters including 5-HT and norepinephrine during emotional distress [178]. Psychological stress drives gut microbial dysbiosis, notably depleting Akkermansia muciniphila and butyrate, to promote breast tumor growth and cancer stemness. Mechanistically, butyrate suppresses the Wnt/β-catenin pathway by downregulating LRP5 via zinc finger protein 36 homolog (ZFP36)-mediated mRNA decay and histone deacetylases (HDAC) inhibition. Clinically, low A. muciniphila and butyrate correlate with poor prognosis and negative mood in patients. These findings reveal a microbiota-stress-cancer axis and highlight microbial and metabolic interventions as potential therapies [179]. Moreover, it was identified that chronic stress alters oral bacteria such as the enrichment of Pseudomonas and Veillonella and depletion of Corynebacterium and Staphylococcus in head and neck squamous cell carcinoma (HNSCC), further causing the oral and gut barrier dysfunction. This interaction leads to the deubiquitination and stabilization of the aryl hydrocarbon receptor (AhR), which enhances the synthesis of kynurenine (Kyn) in CD8+ T cells, thereby promoting their exhaustion [180]. After prolonging stress in the prefrontal cortex area, the microbiota innate lymphoid cell type 3 (ILC3)-Treg axis has been generated and empowers the TME [181, 182]. In addition, chronic stress can disrupt the balance of gut bacteria, for example reducing the growth of Lactobacillus plantarum (L. plantarum) responsible for CD8+T cells in gut [183]. The expression of β-catenin in stress decreases Lactobacillus johnsonii (L. johnsonii) and its metabolite protocatechuic acid (PCA) in colorectal cancer progression [184]. Chronic stress via glucocorticoids, leading to decreased luminal guanine and subsequent suppression of Bifidobacterium proliferation. The resulting impairment in Bifidobacterium-mediated oleic acid degradation elevates serum oleic acid levels, thereby facilitating tumor metastasis [185]. In summary, chronic stress and its associated hormones facilitate tumorigenesis through the modulation of microbial homeostasis. These findings suggest that microbiome-based biomarkers or probiotic interventions may help alleviate stress in cancer prevention and treatment.

Drug resistance

Chronic stress promotes an inflammatory and immunosuppression state, which can contribute to the resistance of cancer treatment [186, 187]. Chronic stress can enhance tumor cells resistance to radiation, immunotherapy and chemotherapy drugs by interfering with apoptosis through the activation of β-AR signaling [26, 141, 188, 189]. Increased norepinephrine inhibits CD8+ T cell chemotaxis, leading to resistance to PD-1 therapy. It also affects tumor cell secretion of CXCL9 and adenosine, further supporting PD-1 therapy resistance [121]. Epinephrine-induced pathways like cyclic adenosine monophosphate (cAMP)-dependent PK and BCL2-associated agonist of cell death (BAD) phosphorylation also defend cancer cells from apoptosis [190]. Epinephrine and norepinephrine influence cytochrome P450 through adrenergic pathways, altering the pharmacokinetics and potency of various drugs [191]. Additionally, they reduce the efficacy of gemcitabine resistance by downregulation β2-AR/glycolysis axis in intrahepatic cholangiocarcinoma [192]. Moreover, α-ARs increase multidrug resistance protein 1 (MDR1) causing the resistance to paclitaxel, while β2-ARs triggered trastuzumab resistance via PI3K/AKT/mammalian target of rapamycin (mTOR) axis [193]. In correlation with β2-AR, cancer cells also show resistance against epidermal growth factor receptor (EGFR) antagonists and tyrosine kinase inhibitors (TKIs) [194–196]. However, glucocorticoids increase ROR1 impairment leading to taxanes (chemotherapeutics) and second mitochondria-derived activator of caspases (SMAC) mimetics (anti-apoptotic) drug resistance [197]. Furthermore, in therapy-resistant prostate cancers, glucocorticoids can substitute for androgens by activating mutant androgen receptor (AR) variants, driving cell proliferation and prostate-specific antigen (PSA) secretion even in the absence of testosterone [198]. Meanwhile, glucocorticoid receptor activation drives resistance to AR-directed therapy in castration-resistant prostate cancer (CRPC) by upregulating anti-apoptotic targets serum and glucocorticoid-regulated kinase 1 (SGK1) and dual specificity phosphatase 1 (DUSP1), sustaining tumor cell viability and PSA secretion [199]. Its upregulation also promotes prostate cancer cells evade enzalutamide treatment via a tissue-specific enhancer [200]. Glucocorticoids drive upregulation of the therapy-resistance oncoproteins lens epithelium-derived growth factor p75 (LEDGF/p75) and clusterin (CLU) in prostate cancer cells via GR activation. Moreover, enhanced GR expression in African American versus European American tumors suggests that heightened glucocorticoid signaling may contribute to racial disparities in prostate cancer progression and treatment resistance [201]. Chronic stress also affects oxidative stress pathways to complicate treatment, making it less effective in targeting cancer cells like HIF and nuclear factor erythroid 2-related factor 2 (NRF2) to promote drug resistance [202, 203]. In lung tumorigenesis, olanzapine (OLZ) application suppresses chronic stress/norepinephrine-induced gemcitabine resistance in lung cancer malignancies. Moreover, OLZ attenuates the mPFC/norepinephrine/circadian locomotor output cycles kaput (CLOCK) axis to mitigate chronic stress–associated anxiety-like behaviors and lung cancer stemness in the Kras^{LSL−G12D/WT} lung cancer mouse tumor model [204]. Hence, chronic stress and stress hormones have crucial effects on drug resistance in cancer therapeutics.

Epidemiological evidence of chronic stress in cancer

Some retrospective or prospective studies support evidence about the role of stress as an initiator in malignant transformation (Table 2). For example, A 15-year study of 10,808 Finnish women found that those experiencing major stressful life events over 5 years, out of which 180 incidents were reported of breast cancer diagnosis [205]. Furthermore, 10 year before diagnosis of 115 Finnish women [206] had significantly higher breast cancer incidence. Among men aged 65 and older, elevated workplace stress is associated with an increased risk of prostate cancer [207]. A study of 6,248 Jewish individuals found that psychological stress may increase the risk of lymphatic, hematopoietic, and skin cancers [208]. Post-traumatic stress disorder is significantly associated with ovarian cancer [209]. In a recent cross-sectional study of 121 Black and White women with breast cancer and high perceived stress, elevated IL-6 levels (a pro-inflammatory cytokine) and increased M2 macrophage infiltration (a pro-tumor phenotype) were both significantly correlated with tumor mutational burden in the immune microenvironment [42]. However, during diagnostic phases, breast cancer in metastatic stage is significantly associated with anxiety symptoms [210]. Cancer patients with pre-existing stress exhibit a 1.3-fold higher mortality rate, however, it is varied by cancer stage and type [28]. Some analyses have revealed a possible significant association between stressful life events and risky lifestyle behaviors, such as alcohol consumption, smoking, and unhealthy diets in increasing cancer risk [211]. Moreover, A larger meta-analysis linked psychosocial factors and stress to higher cancer incidence, poorer survival, and increased mortality [20, 27, 212]. Therefore, existing epidemiological data supports the potential role of chronic stress in promoting tumor development.

Table 2.

Epidemiological characteristics of stress-cancer relevant studies

Article Type	Sample	Cohort	Clinical Relevance	Stress measures	Cancer type	Reference
Prospective	10,808 women	Finnish Twin Cohort	Accumulation of stressful life events contribute to breast cancer etiology, potentially via hormonal or related biological pathways	Modified standardized life event inventory	Breast cancer	[205]
Prospective	115 participants	Women with breast symptoms at Kuopio University Hospital	Significant association between stressful life events and cancer risk, possibly via stress-induced disturbances in immune surveillance	Beck Depression and Spielberger Trait Inventory and interview	Breast cancer	[206]
Case-control	1,933 cases 1,994 controls	Canadian men cohort	Significant association between continuous stress at the workplace and an increase in risk of cancer	Workplace stress-related question	Prostate cancer	[207]
Prospective	6,284 participants	Jewish Israeli parents who lost an adult son	Severe bereavement is associated with higher incidence of certain malignancies, or accelerates mortality	Bereavement Questions	Different cancer types	[208]
Prospective	54,710 women	Nurses’Health Study II	Significantly associated between PTSD symptoms and increased risk of ovarian cancer	Trauma Interview with modification	Ovarian cancer	[209]
Retrospective	567 patients	Newly diagnosed cancer patients	Significant association between peculiar psychological functioning and risk of cancer	Non-standardized 3-point Likert scale	Breast cancer	[210]
Cross-sectional study	121 participants	Women with breast cancer recruited at two Baltimore hospitals	Significant association between perceived stress, inadequate social support, racial and ethnic discrimination, and neighborhood deprivation and tumor immune environment alteration, particularly for Black women	Cohen 10-item Perceived Stress Scale, 24-item Social Provisions Scale,	Breast cancer	[42]
Retrospective	26,497 participants	Stress-related cancer patients	Significant association between preexisting stress-related diagnoses and increased rates of incidence of mortality	International Classification of Diseases, Tenth Revision (ICD-10)	Different cancer types	[28]
Case-control	157 cancer cases and 314 controls	Newly diagnosed breast cancer patients	Perceived stress, especially when coupled with adverse lifestyle behaviors, may contribute to breast cancer etiology	Stress Related Question	Breast cancer	[211]
Meta analysis	99,807 women	7 studies	Women who experience striking life events face a roughly 1.5-fold increased risk of primary breast cancer	Literature review	Breast cancer	[212]
Meta analysis	548 studies	165 study cohorts to analyze cancer incidence, 330 to analyze survival, and 53 to analyze cancer mortality	Stress-related psychosocial factors are linked to higher cancer incidence, poorer survival, and increased mortality, with site-specific effects	Literature review	Different cancer types	[20]
Meta analysis	2,611,907 participants	51 eligible cohort	Depression and anxiety may have an etiologic role and prognostic impact on cancer	Literature review	Different cancer types	[27]

A new horizon: stress-associated obesity in cancer

Stress-induced activation of the nervous system triggers glucocorticoid release, which drives cravings for high-fat, high-sugar, high-calorie foods and ultimately promotes obesity [213, 214]. While obesity causes DNA instability [215], it also fosters a pro-tumorigenic environment via chronic oxidative stress and sustained chronic low-grade inflammation. Both of which drive tumor progression and immune evasion through pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α. In obesity, prolonged lipid overaccumulation causes adipocytes to expand beyond their vascular support capacity leading to adipocyte cell death through necrosis [216]. The release of inflammatory chemokines and cytokines as a result of adipocyte death. Adipocyte death releases inflammatory chemokines and cytokines that recruit M1-polarized macrophages into adipose tissue. These macrophages then sustain chronic, low-grade inflammation by secreting additional proinflammatory factors. This inflammatory environment then biases T cell differentiation, promoting the development of proinflammatory Th1 and Th17 while suppressing anti-inflammatory T cell populations [217]. Furthermore, both stress and obesity cause oxidative stress, for example, stress-induced glucocorticoids generate ROS and reactive nitrogen species (RNS), leading to DNA damage and increased cancer risk [218]. However, in obesity, elevated fatty acids induce oxidative stress through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, leading to dysregulation of adipocytokines—such as adiponectin, plasminogen activator inhibitor-1 (PAI-1), IL-6, and monocyte chemotactic protein-1 (MCP-1) [219]. The most recent research revealed the connection between chronic stress and obesity. It showed that chronic stress–induced norepinephrine signaling in mice fed an obesogenic high-fat, high-calorie diet. The β-AR agonist isoproterenol synergize with obesity to drive pancreatic cancer development by activating PKA-mediated phosphorylation of CREB at Ser133 [220]. Furthermore, a meta-analysis revealed that obesity is directly proportional to the increased mortality rate in cancer patients [47]. Hence, obesity promotes tumors progression by mediating inflammation, oxidative stress, and an immunosuppressive microenvironment, which parallels the mechanisms by which chronic stress drives cancer progression. However, the bidirectional crosstalk between chronic stress and obesity, forming a self-reinforcing nexus of neuroendocrine and metabolic dysregulation, emerges as a critical frontier for future cancer research.

Concluding remarks

Emerging evidence suggests chronic stress promotes tumorigenesis, though its role as an etiological driver of cancer progression remains hypothetical. Key physiological stress responses, particularly involving catecholamines and glucocorticoids, appear to facilitate cancer development through multiple mechanisms. These stress mediators activate downstream signaling pathways via their respective receptors, potentially favoring tumor progression at various biological levels. These biological processes include enhanced cell proliferation and survival, suppressed immune surveillance, increased angiogenesis, promotion of metastatic processes. Moreover, the advances in preclinical models and clinical translation now demonstrate that integrating anti-stress interventions with standard antitumor therapies can improve cancer treatment outcomes (Table 3). Evidence indicates that using propranolol (β-blocker) could reduce stress in cancer patients [221–224]. Moreover, preoperative use of β-blocker inhibiting Treg responses [225], and attenuates EMT and tumor-infiltrating cells like CD14+ monocytes, CD19+ B cells, increases CD56+ NK cells [226]. Furthermore, β-adrenergic antagonists such as propranolol are well studied alone or in combination with anti-cancer drugs. Many clinical trials have investigated the efficacy and tolerance of propranolol 20 mg twice daily in prostate cancer (NCT05679193), CD34+ cell–associated and relative downregulation of myeloid progenitor–containing CD33+ cell–associated gene transcripts with titration between 20 and 40 mg in multiple myeloma (NCT02420223) [222] and invasive EOC at 40 mg twice daily (NCT01308944). Comparison between physical activity, nutrition, beta blocker is also recruiting in myeloma patients (NCT05312255). In NCT01504126, the blockade of adrenergic response via propranolol (20 mg, twice daily) combination with chemotherapy is also used to boost immune system by decreasing in serum IL-6, IL-8, and IL-10 in ovarian cancer patients [227], other combinations of propranolol (30 mg twice daily) with immunotherapeutic drug (Pembrolizumab, 400 mg, intravenously) chemotherapy drugs (FOLFOX, every two weeks) is recruiting NCT05651594. Moreover, stress, as measured by the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder 7-item (GAD-7) scale, is associated with poorer outcomes in advanced NSCLC patients receiving immune checkpoint inhibitors. On the basis of these findings, the clinical trial NCT05979818 is now underway [19]. These clinical trials aforementioned highlight the complex link between cancer biology, adrenergic signaling, and stress, suggesting stress-dependent treatment in cancer prevention. However, the evaluation of the combination of propranolol with COX-2 inhibitor (NCT05429970, NCT03919461, NCT03838029), immune checkpoint inhibitors (NCT05968690) are recruiting, this trial’s findings will clarify the efficacy of combining β-blockers with traditional chemotherapy for enhancing treatment outcomes in cancer patients in immune context. Glucocorticoids antagonists are now also under research in cancer treatment to eliminate the influence of stress [57]. The clinical usage of glucocorticoid antagonist mifepristone (300 mg daily) in combination with androgen antagonist enzalutamide (40/80/120 mg) in patients with metastatic castration resistant prostate cancer demonstrated AR-GR antagonism was safe and well tolerated (NCT02012296) [228]. In addition, clinical trials of relacorilant (NCT02762981, NCT05726292, and NCT04373265) focus on the safety and efficacy of single or combination treatment in different kinds of solid tumors. Moreover, the other glucocorticoid antagonist, CORT125281, combined with enzalutamide was safe and well tolerated in metastatic castration-resistant prostate cancer (NCT03437941) [229].

Table 3.

Clinical trials of adrenergic and glucocorticoids antagonists in cancer therapeutics

Clinical Trial No.	Type of Cancer	Sample Size	Clinical Phase	Status	Aims/Outcomes	Drug/Application
Beta-Adrenergic Antagonists
NCT05679193	Prostate cancer	40	II	Completed	To assess the efficacy of perioperative propranolol capsules in decreasing the recurrence of prostate cancer after RALP Outcome not reported	Propranolol Attenuate surgical stress
NCT02420223	Multiple myeloma	25	II	Completed	To evaluate propranolol’s effect on β-adrenergic gene expression in multiple myeloma patients post-autologous hematopoietic cell transplant Propranolol is effective in the treatment of multiple myeloma	Propranolol Attenuate HCT-related stress
NCT05429970	Ovarian cancer	35	NA	Ongoing	To determine the combination of propranolol and etodolac with mind-body resilience training/mind-body resilience training (MBRT) and music therapy on stressed ovarian cancer patients	Propranolol Etodolac Attenuate perioperative stress
NCT01504126	Ovarian, primary peritoneal, or fallopian tube cancer	32	I	Completed	To determine the effect of propranolol on stimulating the immune system and enhancing chemotherapy Outcome not reported	Propranolol hydrochloride Chemotherapy Attenuate chemotherapy and perioperative stress
NCT05968690	Advanced melanoma	12	I	Ongoing	To determine the effect of propranolol and opioid receptor antagonist (naltrexone) with immune checkpoint inhibitors on advanced melanoma	Propranolol Naltrexone Attenuate immunotherapy stress
NCT01308944	Invasive epithelial ovarian cancer, primary peritoneal carcinoma, fallopian tube cancer	24	I	Completed	To determine if propranolol is tolerable when given with chemotherapy; To understand if behavioral factors can alter blood markers that affect tumor vascularity Outcome not reported	Propranolol Attenuate chemotherapy and perioperative stress
NCT03919461	Colorectal cancer	200	II	Ongoing	To determine the combination effect of propranolol with prostaglandin inhibitor etodolac on metastasis	Propranolol Etodolac Attenuate perioperative stress
NCT05979818	Advanced non-small cell lung carcinoma	6	I	Ongoing	To evaluate the efficacy and safety in a small-dose of propranolol hydrochloride in combination with sintilimab and platinum-based chemotherapy in first-line therapy	Propranolol Sintilimab Chemotherapy Attenuate peri-treatment stress
NCT03838029	Pancreatic cancer	210	II	Ongoing	To determine the effect of propranolol and a COX-2 inhibitor in patients undergoing surgery with primary pancreatic cancer	Propranolol Etodolac Attenuate surgical stress
NCT05312255	Multiple myeloma	175	NA	Ongoing	To determine the effect of propranolol on immune response and quality of life in patients with multiple myeloma	Propranolol Attenuate biobehavioral stress
NCT05651594	Advanced or metastatic esophageal or gastroesophageal junction adenocarcinoma	40	II	Ongoing	To determine the effect of propranolol combined with standard chemotherapy on metastasis	Propranolol Pembrolizumab mFOLFOX Attenuate treatment-related adrenergic stress
NCT02342275	Infantile hemangiomas	377	III	Completed	To compare the efficacy of propranolol versus atenolol in the treatment of potentially disfiguring or functionally threatening IHs Atenolol was as effective as propranolol with fewer adverse events in infants with problematic infantile hemangiomas.	Propranolol Atenolol Inhibit endothelial proliferation
NCT05106179	Spinal hemangioma	1000	IV	Unknown Status	To evaluate the efficacy and safety of β-blockers drugs in adults with spinal hemangioma Outcome not reported	Atenolol Propranolol Inhibit vascular endothelial proliferation
Glucocorticoids Antagonists
NCT02762981	Solid tumors	85	I/II	Completed	To assess the safety and efficacy of the combination of relacorilant and nab-paclitaxel in participants with solid tumors. Relacorilant upregulates somatostatin receptor subtype 2 expression in ACTH-producing neuroendocrine tumors	Relacorilant Nab-paclitaxel Restore chemotherapy sensitivity
NCT05726292	Prostate Cancer	90	II	Ongoing	To gather information on the safety and effectiveness of combining relacorilant and enzalutamide with hormone therapy	Relacorilant Enzalutamide Restore enzalutamide sensitivity and inhibit tumor progression
NCT02012296	Metastatic hormone-resistant prostate cancer	88	I/II	Completed	To study the side effects and best doses of enzalutamide and mifepristone combination in treating patients with metastatic hormone-resistant prostate cancer. Daily dosing of enzalutamide combined with mifepristone was safe and well tolerated	Mifepristone Enzalutamide Restore enzalutamide sensitivity
NCT03674814	Prostate Cancer	35	I	Ongoing	To study the combination of relacorilant with enzalutamide in patients with metastatic castration resistant prostate cancer	Relacorilant Enzalutamide Restore enzalutamide efficacy
NCT03437941	Metastatic castration-resistant prostate cancer	39	I/II	Completed	To study the safety, tolerability, PK, and PD and preliminary efficacy of CORT125281 in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer Enzalutamide combined with GR antagonist was safe and well tolerated	CORT125281 Enzalutamide Restore AR-directed therapy efficacy
NCT04373265	Adrenocortical Carcinoma	15	I	Completed	To investigate the safety and efficacy of Relacorilant in combination with Pembrolizumab for Patients with Adrenocortical Carcinoma under stress Outcome not reported	Relacorilant Pembrolizumab Antagonizes GR signaling to relieve immunosuppression and enhance pembrolizumab efficacy

As the robust evidence indicates above, chronic stress and stress-related hormones indeed influence cancer hallmarks and promote tumorigenesis. As a result, chronic stress is now recognized as a potential fourth cancer etiology in the latest cancer theory framework. Chronic stress-based tumorigenesis mouse models have been successfully established in ESCC, liver cancer, gastric cancer, breast cancer, colorectal cancer, lung cancer, HNSCC, and IR-induced lymphomas and sarcomas in recent years, and those progress will greatly contribute to the mechanisms study of chronic stress in promoting tumorigenesis. Based on current data, we believe that in-depth research should be done at molecular and mechanistic levels on adrenergic/glucocorticoid antagonists as an adjuvant intervention that gives better inhibition of cancer progression or metastasis. In addition, stable and convincible murine models of chronic stress-linked cancer initiation and progression are the key to comprehensively understanding the underlying mechanism. Chronic stress-associated tumorigenesis studies with the advancement of organoids, 3D cell culture, brain-computer interface, neuron discharge tracing technology, CRISPR technique, and artificial intelligence could hasten the execution against cancer. More efforts should be made to uncover the underlying mechanisms responsible for alleviating mental stress in cancer heterogeneity and transgenic research. Besides, combination studies of pharmacological and non-pharmacological methods with anti-stress medicines need to be explored. Such efforts will help bridge the significant gap in our understanding of how stress-induced alterations in the TME, microbiome and immune response contribute to cancer, ultimately paving the way for novel therapeutic strategies.

Limitations

While emerging evidence implicates the role of chronic stress and stress hormones in promoting tumorigenesis, critical gaps in their etiological mechanisms still remain unclear. Particularly, the precise oncogenic role of stress hormones, whether they function primarily as direct chemical carcinogens or as mediators of psychological stress pathways in tumorigenesis, remains further study. Moreover, although we highlight chronic stress contributions to therapy resistance and gut microbiome dysbiosis, their implications for tumor heterogeneity and anti-stress therapies for cancer prevention demand systematic investigation. Importantly, the tumor-stress relationship is bidirectional: tumors can activate stress responses, creating feedforward loops that complicate causal inference in clinical studies. While promising, beta blockers in anti-cancer therapy in clinical remain investigational. More research and clinical trials are needed to understand the optimal use of beta-blockers in cancer treatment.

Abbreviations

α-AR

Alpha-adrenergic receptor

β-ARs

Beta-adrenergic receptors

4-NQO

4-nitroquinoline 1-oxide

AhR

Aryl hydrocarbon receptor

ALDH

Aldehyde dehydrogenase

AOM

Azoxymethane

AP-1

Activator protein 1

ATF1

Cyclic AMP-dependent transcription factor

ATP

Adenosine triphosphate

BAD

BCL2-associated agonist of cell death

BDNF

Brain-derived-neurotrophic factor

CAF

Cancer-associated fibroblasts

cAMP

Cyclic adenosine monophosphate

CCL

Chemokine (C-C motif) ligand

CDX

Cell-derived xenograft

CEBPB

CCAAT enhancer-binding protein beta

cGMP

Cyclic guanosine 3’,5’-cyclic monophosphate

CLOCK

Circadian locomotor output cycles kaput

CLU

Clusterin

CNS

Central nervous system

COX2

Cyclooxygenase 2

CRPC

Castration-resistant prostate cancer

CREB1

cAMP response element-binding protein 1

CRS

Chronic restraint stress

CSC

Cancer stem cell

CUS

Chronic unpredictable stress

CXCL

Chemokine (C-X-C) motif ligand

CXCR

Chemokine receptor

DUSP1

Dual specificity phosphatase 1

DRD2

Dopamine receptor D2

DSS

Dextran sulfate sodium

EBV

Epstein-Barr virus

ECM

Extracellular matrix

EGFR

Epidermal growth factor receptor

EMT

Epithelial-to-mesenchymal transition

EOC

Epithelial ovarian cancer

ERK

Extracellular signal-regulated kinase

ESCC

Esophageal squamous cell carcinoma

GLUT1

Glucose transporter 1

GR

Glucocorticoid receptor

GSK-3β

Glycogen synthase kinase 3β

H. pylori

Helicobacter pylori

HCC

Hepatocellular carcinoma

HGSC

High-grade serous carcinoma

HIF

Hypoxia-inducible factor

HK2

Hexokinase 2

HMGB

High mobility group box

HPA

Hypothalamic / pituitary / adrenal

HPV

Human papillomavirus

,HSD1

β-hydroxysteroid dehydrogenase type 1

IFN-γ

Interferon-γ

IGF2

Insulin like growth factor 2

ILC3

Innate lymphoid cell type 3

IR

Ionizing radiation

IRF1

Interferon regulatory factor-1

JNK

Janus kinase

Kyn

Kynurenine

LDHA

Lactate dehydrogenase A

LDLR

Low density lipoprotein receptor

LEDGF/p75

Lens epithelium-derived growth factor p75

LEPR

Leptin receptor

LRP1

Lipoprotein receptor-related protein 1

MAPK

Mitogen-activated protein kinase

MCP-1

Monocyte chemotactic protein–1

MDR1

Multidrug resistance protein 1

MDSc

Myeloid-derived suppressor cells

MHC

Major histocompatibility complex

MMP

Matrix metalloproteinases

mPFC

Medial prefrontal cortex

mROS

Mitochondrial reactive oxygen species

mTOR

Mammalian target of rapamycin

NADPH

Nicotinamide adenine dinucleotide phosphate

NF-κB

Nuclear factor kappa-light-chain-enhancer of activated B cells

NGF

Nerve growth factor

NRF1

Nuclear respiratory factor 1

NRF2

Nuclear factor erythroid 2-related factor 2

NSCLC

Non-small-cell lung cancer

OLZ

Olanzapine

PAI-1

Plasminogen activator inhibitor–1

PCA

Protocatechuic acid

PD-1

Programmed cell death protein-1

PD-L1

Programmed cell death ligand-1

PFKP

Phosphofructokinase, platelet

PGE2

Prostaglandin E2

PI3K

Phosphatidylinositol 3-kinase

PK

Protein kinase

PLAGL2

Pleomorphic adenoma gene like-2

PSA

Prostate-specific antigen

ROR1

Receptor tyrosine kinase-like orphan receptor 1

SGK1

Serum and glucocorticoid-regulated kinase 1

sFRP1

Secreted frizzled-related protein 1

SIRPα

Signal regulatory proteinα

SMAC

Second mitochondria-derived activator of caspases

SNS

Sympathetic nervous system

STAT

Signal transducer and activator of transcription

TEAD4

TEA domain transcription factor 4

TAM

Tumor-associated macrophages

TGF-β1

Transforming growth factor‑β1

TIDCs

Tumor-infiltrating dendritic cells

TIL

Tumor infiltrating lymphocyte

TKI

Tyrosine kinase inhibitor

TLR4

Toll-like receptor 4

TME

Tumor microenvironment

TNF-α

Tumor necrosis factor-α

TRIM

Tripartite motif

TH

Tyrosine hydroxylase

USP10

Ubiquitin-specific protease 10

UV

Ultraviolet

VDCC

Voltage-dependent calcium channel

VEGF

Vascular endothelial growth factor

VTA

Ventral tegmental area

ZFP36

Zinc finger protein 36 homolog

RNS

Reactive nitrogen species

PHQ-9

Patient Health Questionnaire-9

GAD7

Generalized Anxiety Disorder 7

ARRB1

Arrestin beta 1

BRCA1

Breast cancer gene 1

MDM2

Murine double minute 2

TNBC

Triple negative breast cancer

GRP78

Glucose-regulated protein 78

HNSCC

Head and neck squamous cell carcinoma

HDAC

Histone deacetylases

5-HT

5-hydroxytryptamine/serotonin

NETs

Neutrophil extracellular traps

Author contributions

All authors made substantial contributions to this review. A.K. and M.Q. S wrote this review and organized the figures, Z.G.D provided editorial assistance. All authors read and approved of the final manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82073075), the Project of Zhongyuan Scholar Talent (No.234000510008), the Major Science and Technology Projects in Henan Province (No. 221100310100), the Henan Provincial Science and Technology Research Project (No.242102311218), and the Postdoctoral Science Foundation of China (No. 2023M733222).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.