CHRONIC STRESS AS A MODULATOR OF THE TUMOR IMMUNE MICROENVIRONMENT

Abstract

Chronic psychological stress is increasingly recognized as a biological modifier of cancer progression through sustained neuroendocrine and immune dysregulation. This narrative review summarizes current evidence on how chronic activation of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system reshapes the tumor immune microenvironment and may influence response to anticancer therapy. Glucocorticoid and adrenergic signaling can alter immune -cell trafficking, differentiation, metabolism, and effector function, promoting expansion or functional reprogramming of tumor -associated macrophages, myeloid -derived suppressor cells, and neutrophils while impairing cytotoxic T -cell and natural killer - cell activity. Experimental studies provide particularly strong evidence for glucocorticoid-dependent neutrophil reprogramming and neutrophil extracellular trap ormation as mechanisms linking chronic stress with prometastatic microenvironmental changes. Persistent beta -adrenergic signaling may additionally promote metabolic dysfunction and exhaustion of tumor-infiltrating T cells. Emerging clinical studies in mel anoma and non- small-cell lung cancer have associated pretreatment emotional distress with inferior outcomes during immune checkpoint blockade; however, these observations remain non- causal. Current evidence supports chronic stress as a potentially modifiab le component of tumor -immune interactions, but prospective mechanistic and interventional studies are required before stress - related parameters or adrenergic modulation can be used as validated predictive or therapeutic tools in oncology.