Schematic diagram of the potential mechanisms by which neuropsychological stress promotes central nervous system tumor recurrence via the blood-brain barrier

Neuropsychological stress activates the hypothalamic-pituitary-adrenal (HPA) axis and the sympatho-adrenal-medullary (SAM) axis the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, leading to the systemic release of stress-induced factors such as cortisol, norepinephrine (NE), and epinephrine (Epi). These factors compromise the integrity of the blood-brain barrier (BBB) by inducing tight junction degradation, which subsequently facilitates the entry of circulating pro-inflammatory cytokines into the brain parenchyma extravasation of pro-inflammatory cytokines and the infiltration of immunosuppressive cells into the brain parenchyma.

In the brain, this cascade triggers the remodeling of the tumor microenvironment (TME) surrounding minimal residual disease. The recruitment and interaction of microglia, M2 macrophages, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and cancer-associated fibroblasts result in the robust secretion of pro-angiogenic factors and immunosuppressive factors (e.g., TGF-β, IL-10, VEGF). This highly immunosuppressive TME may promote the re-entry of dormant tumor cells into the cell cycle awakens dormant tumor cells, promotes cellular proliferation, and drives tumor invasion and expansion, leading to CNS tumor recurrence.