Over the past several decades, a profound transformation has been observed in cancer epidemiology, with the disease emerging as the foremost cause of mortality on a global scale (1). Cancer, a significant non-communicable disease posing a substantial public health challenge, predominantly arises from the intricate interplay between environmental determinants and genetic predispositions (2). Advanced genomic sequencing initiatives have unveiled the complex genomic landscape of human cancers, highlighting that specific intragenic mutations, known as “driver mutations,” can instigate or “drive” tumorigenesis (3). A typical tumor harbors 2 to 8 such “driver gene” mutations, which confer a selective growth advantage, while the remaining mutations are considered “passenger” mutations, making no significant contribution to tumor progression. Epidemiological investigations have pinpointed a multitude of environmental carcinogens, spanning from infectious agents to modifiable lifestyle factors such as tobacco use, alcohol consumption, obesity, and unhealthy dietary and physical activity patterns (4). Notably, beyond established risks such as smoking and diet, chronic psychological stress is increasingly recognized as a key regulator of cancer progression, primarily through its disruption of antitumor immunity.

Stress encompasses a spectrum of neuroendocrine responses, predominantly characterized by sympathetic nervous system excitation and augmented pituitary-adrenocortical secretion (5). It also encompasses a suite of nonspecific reactions that the body initiates when confronted with intense stimuli (6). Recent narrative review has further provided a detailed description of this perspective, highlighting the mechanisms whereby stress-mediated neuro-endocrine pathways result in allostatic overload, thereby manifesting the substantial research significance in this domain (7). Stress is categorized into acute and chronic forms. Acute stress typically arises during emergencies, such as when faced with threats or challenges, and it manifests as an enhancement of protective mechanisms. This transient response is generally advantageous for the body (8). In contrast, chronic stress results from an individual’s prolonged and repeated exposure to various stressors over an extended period. The physiological ramifications of chronic stress include but are not limited to, the sustained activation of the neuroendocrine system (9). Specifically, it involves the hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to a chronically elevated release of cortisol and other stress hormones (10). This neuroendocrine cascade directly orchestrates immunosuppression by dysregulating immune cell function and disrupting the cytokine network, thereby fostering a permissive microenvironment for tumor development (11).

Chronic stress has a profound effect on the overall risk of developing cancer, which is particularly pronounced in men and shows a worrying trend towards younger age groups (12, 13). For example, chronic stress, especially social stress, significantly increases the risk of breast cancer and exacerbates the disease phenotype (14). With the research in this field continues to advance, chronic stress has increasingly been demonstrated to exert pro-tumorigenic effects across multiple cancer types, through mechanisms such as enhanced tumor growth, metastasis, and therapy resistance (15). Epidemiologic studies have shown that cancer patients are more likely to suffer from depression and anxiety compared to the general population, which is complementary with the idea that chronic stress contributes to cancer incidence and progression (16, 17). In recent years, scientific studies have increasingly focused on the role of chronic stress in cancer development. A large body of evidence suggests that chronic stress is not only a potential risk factor for cancer development but may also promote tumor growth, invasion and metastasis (18). This review aims to synthesize the mechanisms by which chronic stress subverts anti-tumor immunity to drive cancer progression. We will focus on how stress hormones remodel the tumor immune microenvironment, inhibit systemic immune surveillance, and ultimately compromise therapeutic efficacy, thereby highlighting potential avenues for intervention.

A search of the related literature was conducted on the PubMed database using the keywords “Neuroimmune Interaction”, “Chronic Stress”, and “Tumor Progression”, which yielded the following search criteria:((“neuroimmune interaction”[All Fields] OR “neural immunity”[All Fields] OR “neuroimmunity”[All Fields] OR “Neuroimmune Interactions”[MeSH Terms] OR “nerve immunity crosstalk”[All Fields]) AND (“chronic stress”[All Fields] OR “chronic psychological stress”[MeSH Terms] OR “chronic stress disorder”[All Fields]) AND (“tumor progression”[All Fields] OR “neoplasm progression”[MeSH Terms] OR “cancer progression”[All Fields] OR “metastasis”[All Fields]) AND 2010/01/01:2025/12/31[Date-Publication]) AND (english[Filter]).

Literature not directly related to the impact of chronic stress on tumor progression was excluded. The authors acknowledged that this retrieval strategy might have inadvertently missed important research papers. Figure 1 presents the PRISMA table, which further illustrates the research sampling procedures by systematically listing the number of literature and key bases at each stage of retrieval, deduplication, screening, and final inclusion, thereby enhancing the transparency and traceability of the literature screening process (19).

A large number of epidemiological studies have revealed significant associations between chronic stress states, such as depression and anxiety, and a poor prognosis for tumors (Table 1). A systematic review showed that the prevalence of depression in cancer patients was as high as 12.5%, which is four times higher than in the general population (32). Similar trends have been found in epidemiological studies of anxiety. Notably, anxiety symptoms had a particularly significant and consistent effect on gender-related cancers. A multicenter cohort study showed that patients with bladder and testicular cancer exhibited higher levels of anxiety. Compared to the general population, bladder cancer patients were 5.3 times more likely to experience anxiety, while testicular cancer patients were 5.0 times (33). Furthermore, several studies have demonstrated a higher prevalence of anxiety symptoms among breast cancer patients, with odds ratios (OR) ranging from 2 to 6. In addition to its effects on tumor formation, a follow-up study at the MD Anderson Cancer Center found that patients with a chronic negative mood had a 32% higher rate of cancer recurrence and significantly higher levels of inflammatory factors in their serum (e.g. IL-6) than the control group (11, 34). Elevated IL-6 levels were notably strongly associated with the progression of eight malignant tumors, including breast and colorectal cancer. An epidemiological survey of 8,387 participants aged 51–61 found that those diagnosed with cancer were at the highest risk of developing depressive symptoms within two years of their initial diagnosis compared to individuals diagnosed with common chronic diseases such as diabetes, hypertension, and heart disease (35). This suggests that chronic stress may affect tumor progression to some extent. However, rigorously designed prospective cohort studies are still needed to validate this association further.

Several meta-analyses and large cohort studies have confirmed that chronic stress has a significant, heterogeneous effect on tumor progression. This heterogeneity manifests in two main aspects: firstly, different forms of chronic stress have entirely different effects on tumors, and secondly, the same type of stress affects different tumors differentially. Specifically, the pooled results of 24 studies revealed that depressive symptoms were associated with a 15% increase in overall cancer risk, a 20% increase in liver cancer risk, and a 33% increase in lung cancer risk (36). Job stress was also found to significantly increase the risk of colorectal, lung and esophageal cancers (37). While anxiety and depression are common symptoms of chronic stress, there are other types of chronic stress. For instance, childhood trauma can increase the risk of brain tumors by 90% (38). Furthermore, studies of cervical precancerous lesions have found that psychosocial stress, such as marital conflict, increases lesion risk by 2.5-fold and that this effect is independent of traditional risk factors, such as human papillomavirus (HPV) infection (39). These results were validated in twin cohort studies: major life events such as divorce or bereavement increased women’s breast cancer risk by 40% (40). Furthermore, when occupational chronic psychological stress levels were high, serum heat shock protein 70 (HSP70) expression levels decreased while tumor necrosis factor-α (TNF-α) expression levels increased, suggesting a decrease in the organism’s emergency response capacity (41).

There are prominent differences between men and women in terms of how they perceive stress and their biological responses to it. These differences can impact cancer incidence, development and heterogeneity (42). The link between chronic stress and female tumors, particularly breast and gynecological tumors, shows a significant cumulative effect. Depressive symptoms can triple the risk of treatment non-adherence in breast cancer patients, and preoperative depressive symptoms are strongly associated with significantly elevated IL-6 levels following surgery (43). Studies have also found that major life events, such as the death of a loved one, personal injury or illness, and legal disputes, can significantly increase the risk of breast cancer. Individuals with a cumulative stress score of over 210 have a 5.09-fold increased risk of breast cancer (44). Furthermore, a prospective cohort study revealed that women who experienced the death of their mother before the age of 20 exhibited a 31% increased risk of breast cancer (45). In breast cancer patients, increased tumor-infiltrating B cells and T cells were significantly associated with criminal exposure, anxiety symptoms and exposure to adverse childhood events (46). In ovarian cancer patients, social isolation is associated with higher levels of norepinephrine in the tumor microenvironment, which may promote malignant tumor progression, indicating that depression, anxiety and socio-environmental adversity may be potential modifiers of the tumor immune microenvironment for women patients (47). Chronic stress and tumors have distinct patterns of association in men. A related case-control study found that occupational frustration, marital separation and being highly sensitive to others’ evaluations significantly increased the risk of prostate cancer (48). Another study showed that men with job stress lasting more than 30 years had a 40% increased risk of prostate cancer (49). Throughout treatment, men with prostate cancer exhibited a relatively high prevalence of depression and anxiety. Interestingly, there was a rebound increase in the prevalence of depression and anxiety after treatment compared to before, possibly due to anxiety specific to postoperative prostate cancer, such as psychological distress resulting from decreased sexual function (50). Meanwhile, men who had experienced a major stressful event in the previous five years were 2.21 times more likely to develop lung cancer (51).

However, epidemiological findings should be interpreted with caution. Reverse causality and behavioral confounders may exaggerate the strength of the association between psychological stress and cancer (52). For example, chronic stress may promote gastric cancer invasion and metastasis by activating the SNS and HPA axis, and is therefore a potential pathogenic factor. Meanwhile, gastric cancer itself and its treatment (e.g. gastrectomy) can also induce depressive symptoms (53). Studies have shown that approximately 57% of gastric cancer patients experience depression, creating a vicious cycle of “stress-cancer-stress” (54). Notably, various confounding factors, including behavioral factors and differences in access to healthcare resources, often confuse such studies. For instance, some studies have demonstrated that, while cancer risk is elevated in populations experiencing depression, the strength of the association between depression and cancer is significantly reduced when behavioral factors such as smoking and alcohol abuse are taken into account (44). Therefore, behavioral factors must be adequately considered in future multivariate statistical models.

Experiments indicate that under chronic stress conditions, excessive secretion of stress hormones can promote the proliferation, migration, and metastasis of tumor cells (52). These promotion effects are mainly mediated by modulating the tumor microenvironment (55). Chronic stress can reprogram metabolic pathways and modify the composition and properties of the tumor microenvironment (Figure 4). These changes contribute to immunosuppression and immune evasion, thereby promoting tumor progression (Figure 5). Collectively, the mechanisms described above constitute a set of complex and parallel pathways through which chronic stress exerts its pro-tumorigenic effects (Table 2).

Conventional cancer treatment strategies include surgical resection, chemotherapy and radiotherapy, which have been employed in clinical practice for decades, while these approaches are often associated with significant adverse effects (110, 111). In recent years, with the development of technology, novel immunotherapies and targeted therapies have appeared. When used as an adjunct to these conventional treatments, these modern approaches have substantially mitigated adverse reactions (112, 113). Despite their widespread clinical application, clinical evidence indicates that chronic stress negatively impacts the efficacy of several of these treatment modalities, including chemotherapy, radiotherapy, immunotherapy, and targeted therapy.

Chronic stress mediated by stress hormone receptor signaling pathways is a significant driver of immunosuppression that ultimately results in immune evasion and enhanced metastatic potential. Consequently, targeting key neuroendocrine pathways has become a crucial strategy to elevate cancer prognosis. A growing number of evidence has demonstrated that β-AR antagonists can effectively block the pro-tumorigenic responses mediated by chronic stress and exhibit broad-spectrum anti-tumor activity across various tumor models (135, 136). Among them, the classical agent propranolol has been shown to reverse tumor treatment resistance (137). Among the multiple cancer metastasis models, propranolol blocks the β2-ARs on monocytes facilitates their functional maturation with upregulated expression of MHC class II to counteract the immunosuppressive effect driven by chronic stress (138). These modified monocytes exhibit enhanced tumor-antigen presentation efficiency, which drives CD4+ T cells into a cytotoxic Th1 phenotype with direct tumoricidal capabilities (138). Similarly, the active component of the traditional Chinese medicine Radix bupleuri, saikosaponin D, also functions to reverse drug resistance modulating glucose metabolism and drug efflux through the inhibition of β2-AR signaling (139). Whether employed as a primary or adjunctive therapy, β-AR blockers have shown remarkable clinical potential (140). Meanwhile, nuclear receptor antagonists targeting glucocorticoid signaling have also demonstrated therapeutic activity in various malignancies (141). In stance, highly selective agents, such as ORIC-101, have exhibited synergistic effects when combined with conventional chemotherapeutics (e.g., paclitaxel), further highlighting their translational promise (141, 142).

Beyond direct antagonism of stress hormone receptors, a complementary and critical strategy is to intervene at the source by targeting chronic stress itself (143). Existing researches suggest that antidepressant therapies may exert cross-indication anti-tumor potential in cancer treatment, though their underlying mechanisms and clinical value require further investigation (144, 145). For example, the selective serotonin reuptake inhibitors (SSRIs), as a common class of conventional antidepressants, have been shown to improve the anti-tumor immune response by enhancing cytotoxic T-cell activity through the inhibition of the serotonin transporter (SERT) (146). The inhibition of the SERT disturbs the homeostatic reuptake of 5-HT, resulting the extracellular accumulation of this monoamine within the interstitial spaces of the central nucleus in the amygdala to inhibit the release of CRH (147). It directly suppresses the over-reaction of HPA axis under the effect of chronic stress. However, the long-term use of SSRIs may present severe adverse effects, including serotonin syndrome and hyponatremia, which pose significant concerns regarding chronic administration safety (148). Beyond these classical antidepressants, several natural plant-derived bioactive compounds have been considered as potential alternatives due to their lower toxicity and antidepressant effects (149, 150). Quercetin can downregulate the voltage-gated calcium channel subunit α2δ-1, which in turn disrupts its interaction with the N-methyl-D-aspartate receptor (NMDAR) to finally achieve the resistant against depression (151, 152). Because of the disconjunction between the α2δ-1 and NMDAR, the synaptic localization of NMDARs and NMDAR-mediated excitatory Ca²⁺ influx are reduced, leading to decrease the CRH release by inhibiting excitability of CRH neuron (151). Similarly, the St. John’s wort (SJW) extract Ze 117 has been widely recognized as a natural alternative for synthetic antidepressants, which has demonstrated well-defined antidepressant efficacy (153). As a potent inhibitor of neurotransmitter, the SJW enhance the synaptic availability of 5-HT, dopamine, GABA and glutamate, which contributes to maintain the central neurotransmitter homeostasis under chronic stress, also partially reversing the excessive activation of the HPA axis caused by chronic stress the central level (154).

In addition, psychosocial and behavioral interventions provide a non-pharmacological novel strategy to counteract the pro-tumorigenic effects induced by chronic stress by restoring the homeostasis of the neuroendocrine–immune axis. The softer approaches such as music therapy, massage, aromatherapy and acupuncture have been shown in clinical trials to alleviate depressive and anxious symptoms while reducing dependence on antidepressant medication (155). Moreover, the mindfulness-based stress reduction (MBSR) has been demonstrated to significantly decrease psychological stress levels. Its mechanism is thought to involve inhibition of HPA axis activity and subsequent reduction in glucocorticoid levels, thus exhibiting clear translational potential for clinical application (156, 157).

Chronic stress, driven by persistent HPA axis and SNS activation, promotes tumor progression by crippling anti-tumor immunity. Elevated stress hormones act through multiple pathways to foster an immunosuppressive tumor microenvironment, disrupt systemic immune surveillance, and induce oxidative damage. Together, these effects not only accelerate tumor growth but also compromise the efficacy of standard therapies. Therefore, targeting the neuroendocrine-immune crosstalk represents a promising frontier for improving cancer outcomes.

Translating these mechanistic insights into clinical practice requires rational intervention strategies. Pharmacologically, β-adrenergic receptor blockers and glucocorticoid receptor antagonists have shown potential in countering treatment resistance and improving outcomes. In contrast, antidepressants aim to mitigate the central drive of chronic stress. Furthermore, psychosocial and behavioral interventions provide a non-pharmacological approach to normalizing stress hormone levels, often with a superior safety profile. However, a unified strategy is needed to guide the selection and integration of these modalities. To this end, we propose a tiered screening and intervention model. This framework utilizes biomarkers such as salivary cortisol to stratify patients based on their stress burden, enabling the personalized application of the aforementioned strategies.

Although targeting chronic stress presents a promising therapeutic avenue, several challenges remain. Firstly, current mechanistic insights are derived predominantly from preclinical models, which cannot fully recapitulate the complexity of the human tumor microenvironment. Secondly, the universality of these mechanisms across diverse cancer types is still uncertain. Future research should prioritize integrating large-scale clinical and genomic data to identify conserved stress-responsive pathways, followed by validation in more human-relevant models. Additionally, the mechanistic basis of psychosocial interventions and the fundamental neurobiology of sustained stress axis activation are poorly understood. Addressing these gaps is essential to transition from symptom management to targeted intervention. Finally, the proposed tiered intervention model, while promising, requires rigorous clinical validation and standardized assessment criteria to establish its utility. Overcoming these hurdles will be crucial for integrating stress modulation as a credible dimension of comprehensive cancer care.