Modern life exposes people to persistent social, environmental and occupational stressors. Growing evidence shows that elevated stress disrupts immune homeostasis and increases the risk of multiple disorders, highlighting the interplay between psychological well-being and physical health. Chronic stress is defined as a persistent, nonspecific adaptive response mediated by the central nervous system (CNS) through activation of the hypothalamic–pituitary (HP) axis and the sympathetic nervous system after exposure to stressors, commonly manifesting as anxiety or depression. Chronic stress is increasingly recognized as a major factor in tumor initiation and progression, influencing both endocrine and immune functions. However, despite considerable evidence, the exact mechanisms by which the CNS mediates the link between chronic stress and cancer development remain unclear. Given these challenges, in-depth research is needed on the neuroendocrine–immune pathways that connect chronic stress to cancer.
Researchers at West China Hospital of Stomatology, Sichuan University, report (DOI: 10.1038/s41368-026-00468-x) in the International Journal of Oral Science that chronic stress accelerates oral squamous cell carcinoma (OSCC) by activating the hypothalamic–pituitary–bone marrow (HPB) axis and remodeling the tumor immune microenvironment. Drawing on the UK Biobank cohort, patient serum and tissue samples, and mouse models of chemical carcinogenesis, orthotopic tongue tumors and postsurgical recurrence, the team linked stress-driven pituitary α-melanocyte-stimulating hormone (α-MSH) release to immunosuppression and tumor progression.
In the UK Biobank analysis, anxiety and depression were independently associated with higher head and neck squamous cell carcinoma (HNSCC)–related mortality, and chronically stressed patients had significantly worse overall survival. In patients, serum α-MSH and LOX-1 (lectin-type oxidized low-density lipoprotein receptor 1), a marker of human polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), rose progressively from normal mucosa to oral leukoplakia (OLK) to OSCC and were strongly correlated. Mouse models mirrored these findings: chronic restraint stress (CRS) activated neurons in the hypothalamic paraventricular nucleus (PVN), upregulated pituitary proopiomelanocortin (POMC) in the intermediate lobe, elevated serum α-MSH, expanded bone marrow PMN-MDSCs and accelerated tumor growth. RNA sequencing identified CXCL13 as a key stress-induced chemokine; neutralizing CXCL13 reduced PMN-MDSC accumulation, restored CD8+ T cell infiltration and suppressed tumor growth. Stress also worsened postsurgical recurrence. In tissue microarrays, LOX-1+ PMN-MDSCs increased with clinical stage, tracked with CD68+CD206+ M2 macrophages, inversely correlated with CD8+ T cells and predicted poorer survival. Combining an melanocortin 1 receptor (MCSR) inhibitor (JNJ-10229570) with anti- programmed cell death protein 1 (PD-1) therapy produced the smallest tumors and the greatest CD8+ T cell infiltration while suppressing PMN-MDSCs, without overt toxicity.
The authors said the work reframes chronic stress as an active biological driver of oral cancer rather than a purely psychological burden. They said the HPB axis appears to be engaged early, even at the precancerous stage, and that its activation reprograms the tumor microenvironment toward immunosuppression. They said blocking MCSR interrupted this circuit, restored antitumor immune surveillance and improved responses to PD-1 blockade. They said the single-time-point stress assessments in the UK Biobank mean causality cannot be established and that further studies are needed to validate the pathway in patients.
The findings suggest that circulating α-MSH and LOX-1+ PMN-MDSC density could serve as minimally invasive biomarkers for identifying patients at higher risk of progression or relapse, and that routine assessment of anxiety and depressive symptoms may help flag those needing closer follow-up. Pharmacological MCSR blockade was well tolerated and mitigated anti-PD-1-associated weight loss in mice, supporting combination strategies to improve the low response rates to PD-1/PD-L1 blockade in OSCC. Future work should optimize dosing, identify predictive biomarkers and test combinations with other immunomodulators in clinical trials.
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References
DOI
10.1038/s41368-026-00468-x
Original Source URL
https://doi.org/10.1038/s41368-026-00468-x
Funding Information
National Natural Science Foundation of China (U25A6003, 82472686 and 82273320); Research and Development Program, West China Hospital of Stomatology, Sichuan University (RD-03-202505).
About International Journal of Oral Science
International Journal of Oral Science (ISSN 1674-2818) was founded in 2009 and aims to publish all aspects of oral science and interdisciplinary fields, including fundamental, applied and clinical research. Covered areas include oral microbiology, oral and maxillofacial oncology, cariology, oral inflammation and infection, dental stem cells and regenerative medicine, craniofacial surgery, dental materials, oral biomechanics, oral, dental and maxillofacial genetic and developmental diseases.