Abstract
Metastasis, the leading cause of death in patients with solid tumors, involves the spread of cancer cells to distant organs. While genetic and environmental factors contribute, chronic stress is a crucial factor in metastatic progression by disrupting neuroendocrine, immune, metabolic, and microbial homeostasis. This review synthesizes evidence linking chronic stress to tumor metastasis through three pathways: (1) direct effects on tumor cell metabolism, (2) remodeling of the tumor microenvironment, and (3) dysregulation of the gut microbiota. Describe how activation of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system influence epithelial-mesenchymal transition, immune evasion, and angiogenesis via β-adrenergic and glucocorticoid receptor signaling. Explore how microbial metabolites and barrier dysfunction influence immune and neuroendocrine circuits, creating a pro-metastatic loop. Finally, we highlight therapeutic strategies, including psychological interventions and pharmacologic approaches, to alleviate chronic stress. This review proposes a mechanistic framework linking neuroendocrine signaling, metabolic reprogramming, and the microbiome-immune axis.