Sichuan University team links chronic stress to faster oral cancer in mice via pituitary α-MSH

Researchers at West China Hospital of Stomatology, Sichuan University, report on nature.com that chronic stress accelerates oral squamous cell carcinoma (OSCC) by activating the hypothalamic–pituitary–bone marrow (HPB) axis. The work combines UK Biobank data, patient serum and tissue samples, and mouse models of chemical carcinogenesis, orthotopic tongue tumors and postsurgical recurrence nature.comnature.comnature.comOpen source ↗. The mechanistic part is preclinical: it was carried out in mice.

Stress and survival in patient data

The UK Biobank analysis included 1477 patients with head and neck squamous cell carcinoma, most of them oral subsite cases, and 384,738 cancer-free controls. Chronic stress was defined by elevated PHQ-4 scores, with a positive screen for depression and/or anxiety. According to the publisher's summary of the paper, anxiety and depression were independently associated with higher mortality from these tumors, and chronically stressed patients had significantly worse overall survival.

In patients, serum α-MSH and LOX-1, a marker of human polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), rose progressively from normal mucosa to oral leukoplakia to OSCC and were strongly correlated. OSCC accounts for about 90% of oral cancers, and oral leukoplakia has a reported malignant transformation rate of 11.7%–23.1%. The authors note that cross-sectional data on psychological distress cannot establish causality.

Neuroendocrine circuit and MC5R blockade

In the mouse models, chronic stress activated neurons of the hypothalamic paraventricular nucleus, causing pituitary overexpression of POMC and aberrant secretion of α-MSH. This raised the frequency of PMN-MDSCs in the bone marrow and upregulated the chemokine CXCL13 in the tumor microenvironment nature.comnature.comnature.comOpen source ↗.

The circuit promoted PMN-MDSC recruitment, suppressed CD8⁺ T cell infiltration and skewed macrophages toward an M2 phenotype, producing marked immunosuppression. Under chronic stress, OSCC progression and recurrence were accelerated.

Pharmacological blockade of the melanocortin receptor MC5R with JNJ-10229570 restored antitumor immune surveillance and markedly potentiated PD-1 checkpoint inhibition in these experiments. The authors describe MC5R as a tractable target for improving immunotherapy in stress-associated cancers. The results come from animal models and patient samples, not from a clinical trial of the blockade.