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

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.