image: Social factors presented in the outer circle and physiological factors in the inner circle are common sources of chronic stress. Social factors include poor pre- or post-delivery care, emotional neglect, violence or abuse, bereavement, financial crisis or unemployment, global health burdens, and academic frustration. Physiological factors include proinflammatory factors, pain, microbial and metabolites, glutamic acid, and genetics. DRG, dorsal root ganglia; Gln, glutamine; Glu, glutamic acid.
Credit: ©Science China Press
For decades, the connection between psychological stress and cancer progression has been recognized in clinical practice—yet the biological mechanisms remained poorly understood. Now, a comprehensive review published in Science Bulletin sheds light on how chronic stress systematically reprograms the tumor microenvironment to fuel cancer development and metastasis. Integrating evidence from neuroendocrinology and oncology, the review delineates how stress-activated signaling pathways create a favorable niche for tumors, and suggests that blocking these signals could open new therapeutic avenues.
So how exactly does chronic stress accelerate cancer? The analysis highlights that persistent stress—driven by factors such as financial hardship, cancer-related pain, or inflammation—activates two central neuroendocrine axes: the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. This results in the continuous release of stress mediators, including cortisol and catecholamines (e.g., norepinephrine), which bind to receptors on both tumor and stromal cells, altering their biological functions. Epidemiological studies consistently correlate high-stress populations with increased cancer incidence and mortality, underscoring the clinical significance of these pathways.
“Chronic stress doesn’t only act on cancer cells—it remodels the entire tumor microenvironment,” the authors explain. “Stress mediators dampen immune surveillance, stimulate angiogenesis, and enhance stem-like properties in tumors, effectively building a defense shield against treatments.” For example, in breast cancer, signaling through β-adrenergic receptors boosts tumor stemness and chemoresistance. In pancreatic cancer, stress-induced inflammation promotes an immune-excluded niche, while in ovarian cancer, stress mediators accelerate the formation of metastatic sites.
These effects are driven by diverse mechanisms, including VEGF-mediated angiogenesis, epithelial-mesenchymal transition, suppression of cytotoxic T-cell activity, recruitment of myeloid-derived suppressor cells, and polarization of M2 macrophages. The review underscores that stress establishes a multicellular signaling network that collectively fuels tumor progression.
Stress Management as Adjuvant Therapy
Importantly, the review also highlights potential interventions. Both preclinical and clinical studies suggest that beta-blockers (like propranolol) and behavioral approaches (such as exercise and cognitive behavioral therapy) can interrupt stress signaling, slow tumor growth, and improve the effects of standard therapies. The authors note that stress management may now be seen as part of precision oncology—rather than just supportive care.
The authors highlight key directions for future studies, focusing on the spatiotemporal dynamics of stress signaling, crosstalk among mediators, and individual variations such as genetics, gender, and tumor type. Moving forward, efforts should aim to decode the psychoneuroimmune networks underlying cancer to facilitate the development of targeted therapies that disrupt stress-induced cancer progression.
Journal
Science Bulletin