Chronic stress drives tumorigenesis and progression via central nervous system-mediated neuroimmune circuits

Abstract

Chronic exposure to severe social and environmental stressors is a major risk factor for tumor initiation and progression, yet the central nervous system (CNS)-driven mechanisms linking stress to cancer immunity remain poorly defined. Here, we identify activation of the hypothalamic-pituitary-bone marrow (HPB) axis as a critical driver of oral squamous cell carcinoma (OSCC). Chronic stress activates hypothalamic paraventricular nucleus (PVN) neurons, inducing pituitary overexpression of POMC and aberrant secretion of α‑MSH. This neuroendocrine activation increases the frequency of PMN-MDSCs in the bone marrow and upregulates the chemokine CXCL13 in the tumor microenvironment. Mechanistic studies show that this stress-responsive neuroendocrine circuit remodels the tumor immune microenvironment by promoting PMN-MDSC recruitment, suppressing CD8⁺ T cell infiltration, and skewing macrophages toward an M2 phenotype, collectively establishing profound immunosuppression. Chronic stress further amplifies this axis, accelerating OSCC progression and recurrence. Therapeutic blockade of MC5R restores antitumor immune surveillance and markedly potentiates PD-1 checkpoint inhibition. These findings delineate a previously underappreciated neuro-immune regulatory pathway governing malignant progression and highlight a tractable target for improving immunotherapy efficacy in stress-associated cancers.