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Psychological stress and tumor progression: Molecular mechanisms and therapeutic implications (Review)

  • Authors:
    • Yifei Zhang
    • Yajun Kong
    • Shuanbao Zhao
  • View Affiliations / Copyright

    Affiliations: School of Medicine, Kunming University of Science and Technology, Chenggong Campus, Kunming, Yunnan 650500, P.R. China, Department of Urology, Baoding Rehabilitation Hospital, Baoding, Hebei 071051, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 487
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    Published online on: September 2, 2026
       https://doi.org/10.3892/ol.2026.15842
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Abstract

Psychological stress contributes to tumor progression through a number of biological pathways. Activation of the hypothalamic‑pituitary‑adrenal axis and the sympathetic nervous system induces the release of stress‑related mediators, including catecholamines and glucocorticoids, which regulate tumor development and metastasis. The present review summarizes the molecular mechanisms underlying stress‑mediated cancer progression at the cellular, immune and neural levels. At the cellular level, stress hormones modulate tumor cell proliferation, autophagy, metabolic reprogramming and stemness maintenance through signaling pathways such as dopamine receptor D2 (DRD2)/ERK/β‑catenin and β2‑adrenergic receptor/cyclic adenosine monophosphate (cAMP)/protein kinase A/cAMP‑response element‑binding protein. Within the tumor microenvironment, psychological stress promotes the accumulation of myeloid‑derived suppressor cells, induces T‑cell exhaustion, facilitates M2 macrophage polarization and enhances angiogenesis and lymphatic remodeling, collectively contributing to an immunosuppressive microenvironment. In addition, sympathetic, parasympathetic and sensory neurons directly regulate tumor cell behavior through pseudosynaptic interactions and neurotransmitter release, including glutamate, acetylcholine and norepinephrine, thereby establishing a neuro‑immune‑tumor regulatory network. Based on these mechanisms, emerging therapeutic strategies, including β‑blockers, inhibitors targeting DRD2, lactate dehydrogenase A and G protein‑coupled receptor kinase 3, neuromodulation approaches and psychosocial interventions, have demonstrated potential therapeutic value in preclinical and clinical studies. The present review systematically summarizes the complex molecular pathways associating psychological stress to tumor progression. Despite notable advances, challenges remain in understanding tumor‑specific heterogeneity in stress signaling pathways and the spatiotemporal regulation of neuro‑immune‑tumor interactions. Future studies focusing on multimodal combination strategies may provide novel insights for integrating stress management into comprehensive cancer therapy.
View Figures

Figure 1

Schematic representation of the
ADRB2/cAMP/PKA/CREB signaling cascade. Norepinephrine, a
stress-associated hormone, triggers the activation of the ADRB2,
which then initiates the adenylate cyclase-mediated cAMP/PKA
signaling pathway. Downstream, CREB is phosphorylated and
translocates into the nucleus. This drives higher expression of
genes associated to anti-apoptotic effects (Bcl-2), cell cycle
advancement (Cyclin D1) and autophagy regulation (ATG5, Beclin-1
and LC3B). In parallel, this signaling pathway enhances protective
autophagy through stimulation of the AMPK-ULK1 axis, allowing tumor
cells to survive under nutrient deprivation and hypoxic conditions,
thereby providing a net survival benefit. ADRB2, β2-adrenergic
receptor; cAMP, cyclic adenosine monophosphate; PKA, protein kinase
A; CREB, cAMP response element-binding protein; AMPK, AMP-activated
protein kinase; ULK1, UNC-51-like kinase 1; CRE, cAMP response
element; ATG5, autophagy protein 5; LC3B, microtubule-associated
protein 1 light chain 3β.

Figure 2

Schematic representation of the
ADRB2/PKA/VDCC/Ca2+/IGF2 signaling pathway.
Norepinephrine triggers the ADRB2/cAMP/PKA signaling cascade, which
then activates L-type VDCCs and allows Ca2+ ions to
enter the cell. This Ca2+-dependent exocytosis boosts
IGF2 secretionand the released IGF2 continuously activates the
IGF-1R, ultimately driving the malignant transformation of
pulmonary epithelial cells. ADRB2, β2-adrenergic receptor; PKA,
protein kinase A; VDCC, voltage-dependent calcium channel; IGF2,
insulin-like growth factor 2; IGF-1R, IGF-1 receptor; cAMP, cyclic
adenosine monophosphate.

Figure 3

Schematic representation of the
HIF1A-AS3/HIF-1α positive feedback loop in lung cancer under
chronic stress. Chronic stress increases HIF1A-AS3 expression,
which directly interacts with YBX1 to activate HIF-1α signaling,
thereby initiating downstream oncogenic pathways. HIF-1α, in turn,
transcriptionally upregulates HIF1A-AS3 via its promoter,
establishing a reciprocal positive feedback loop. This loop
promotes tumor cell proliferation, invasion and metabolic
reprogramming, while simultaneously inducing M2-like macrophage
polarization and suppressing phagocytosis, ultimately creating an
immunosuppressive microenvironment that accelerates lung cancer
progression. HIF1A-AS3, hypoxia-inducible factor 1α antisense RNA
3; YBX1, Y-box-binding protein 1; GCs, glucocorticoids; NETs,
neutrophil extracellular traps; ECM, extracellular
matrix.

Figure 4

Schematic overview of how chronic
stress promotes metastasis by triggering NET-dependent ECM
remodeling. Under chronic stress, the body releases
glucocorticoids, which then stimulate neutrophils to form
neutrophil NETs. After NETs are generated, they activate
fibroblasts and thereby increase the production and deposition of
fibronectin in the ECM. In parallel, NETs also promote the
secretion of MMPs, leading to further changes in the ECM.
Collectively, these events support tumor cell migration, invasion
and eventual distant metastatic spread. GCs, glucocorticoids; NETs,
neutrophil extracellular traps; ECM, extracellular matrix; MMPs,
matrix metalloproteinases.

Figure 5

Schematic representation of sensory
neuron-driven pancreatic cancer progression through glutamatergic
pseudosynapses. Sensory nerve terminals form pseudosynaptic
contacts with PDAC cells and release glutamate. The released
glutamate binds to NMDAR2D (GRIN2D) receptors, which are expressed
on the surface of the cancer cells. This binding leads to
Ca2+ influx and, in turn, activates the CaMK IV-CREB
signaling pathway. As a result, tumor proliferation, neural
innervation, cellular invasion and metastatic spread are promoted.
PDAC, pancreatic ductal adenocarcinoma; NMDAR2D/GRIN2D,
N-methyl-D-aspartate receptor subunit 2D; CaMK IV,
calcium/calmodulin-dependent protein kinase IV; cAMP, cyclic
adenosine monophosphate; CREB, cAMP response element-binding
protein.

Figure 6

Schematic representation of
stress-induced angiogenic signaling in prostate cancer. Chronic
stress activates ADRB2 on tumor cells, triggering the
Gs/cAMP/PKA/CREB signaling axis. CREB regulates angiogenesis via
two downstream pathways: the CREB-HDAC2 pathway, in which
HDAC2-mediated epigenetic repression decreases anti-angiogenic
factors TSP1 and PAI2; and the CREB-GRK3 pathway, in which GRK3
suppresses TSP1 and PAI2. Both pathways converge to upregulate
VEGF, a major pro-angiogenic factor, resulting in enhanced
angiogenesis and subsequent tumor growth and progression. Red
arrows indicate upregulation, down arrows indicate downregulation
and black arrows represent promotion or inhibition as indicated in
the diagram. ADRB2, β2-adrenergic receptor; Gs, G protein; cAMP,
cyclic adenosine monophosphate; PKA, protein kinase A; CREB, cAMP
response element-binding protein; HDAC2, histone deacetylase 2;
GRK3, G protein-coupled receptor kinase 3; TSP1, thrombospondin-1;
PAI2, plasminogen activator inhibitor-2; VEGF, vascular endothelial
growth factor.
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Copy and paste a formatted citation
Spandidos Publications style
Zhang Y, Kong Y and Zhao S: Psychological stress and tumor progression: Molecular mechanisms and therapeutic implications (Review). Oncol Lett 32: 487, 2026.
APA
Zhang, Y., Kong, Y., & Zhao, S. (2026). Psychological stress and tumor progression: Molecular mechanisms and therapeutic implications (Review). Oncology Letters, 32, 487. https://doi.org/10.3892/ol.2026.15842
MLA
Zhang, Y., Kong, Y., Zhao, S."Psychological stress and tumor progression: Molecular mechanisms and therapeutic implications (Review)". Oncology Letters 32.4 (2026): 487.
Chicago
Zhang, Y., Kong, Y., Zhao, S."Psychological stress and tumor progression: Molecular mechanisms and therapeutic implications (Review)". Oncology Letters 32, no. 4 (2026): 487. https://doi.org/10.3892/ol.2026.15842
Copy and paste a formatted citation
x
Spandidos Publications style
Zhang Y, Kong Y and Zhao S: Psychological stress and tumor progression: Molecular mechanisms and therapeutic implications (Review). Oncol Lett 32: 487, 2026.
APA
Zhang, Y., Kong, Y., & Zhao, S. (2026). Psychological stress and tumor progression: Molecular mechanisms and therapeutic implications (Review). Oncology Letters, 32, 487. https://doi.org/10.3892/ol.2026.15842
MLA
Zhang, Y., Kong, Y., Zhao, S."Psychological stress and tumor progression: Molecular mechanisms and therapeutic implications (Review)". Oncology Letters 32.4 (2026): 487.
Chicago
Zhang, Y., Kong, Y., Zhao, S."Psychological stress and tumor progression: Molecular mechanisms and therapeutic implications (Review)". Oncology Letters 32, no. 4 (2026): 487. https://doi.org/10.3892/ol.2026.15842
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