Chronic stress drives tumorigenesis and progression via central nervous system-mediated neuroimmune circuits.
- 1State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
- 2State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China. [email protected].
- 3State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China. [email protected].
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.
Related
- SIRT7 Mediated-PTEN Desuccinylation Drives Gastric Tumorigenesis by Activating PI3K/AKT Pathway.
- UPF1-mediated mRNA decay promotes melanoma tumorigenesis through miR-101-3p-dependent destabilization of NANOS1.
- Substance dependence: distinct transcriptomic patterns and neuroimmune system involvement in addiction pathogenesis and progression
- An integrated human forebrain organoid reveals microglia-mediated CD8⁺ T cell recruitment and neuroimmune dysfunction in Alzheimer's disease pathology.
- Pan-neurofascinopathies: a subgroup that mimic other neuroimmune-mediated diseases
BibTeX
@article{yang2026chronic,
title = {{Chronic stress drives tumorigenesis and progression via central nervous system-mediated neuroimmune circuits.}},
author = {Zhixin Yang and Tianqing Wang and Xin Tian and Silu Sun and Shuyu Xiang and Yuting Hu and Dan Yang and Ying Wang and Lin Ye and Hao Xu and Xikun Zhou and Xin Zeng and Qianming Chen and Jing Li},
journal = {International journal of oral science},
year = {2026},
month = oct,
doi = {10.1038/s41368-026-00468-x},
url = {https://europepmc.org/article/MED/42957619},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Chronic stress drives tumorigenesis and progression via central nervous system-mediated neuroimmune circuits.
AU - Zhixin Yang
AU - Tianqing Wang
AU - Xin Tian
AU - Silu Sun
AU - Shuyu Xiang
AU - Yuting Hu
AU - Dan Yang
AU - Ying Wang
AU - Lin Ye
AU - Hao Xu
AU - Xikun Zhou
AU - Xin Zeng
AU - Qianming Chen
AU - Jing Li
PY - 2026
DA - 2026/10/30
JO - International journal of oral science
DO - 10.1038/s41368-026-00468-x
UR - https://europepmc.org/article/MED/42957619
AB - 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.
SN - 1674-2818
SN - 2049-3169
ER -