Chronic stress may fuel mouth cancer through a brain-to-bone-marrow circuit, study in mice suggests

Chronic stress may help mouth cancer grow by switching on a chain of signals that runs from the brain to the bone marrow and ends by weakening the immune system's attack on the tumour. That is the conclusion of a study by researchers at Sichuan University's West China Hospital of Stomatology, published in the International Journal of Oral Science. In mice, blocking one link in that chain shrank tumours and made a standard immunotherapy drug work better.

Doctors have long suspected that psychological stress affects how cancer behaves, but how the brain would exert that influence has been unclear. The new work, led by Jing Li and Qianming Chen, tries to trace the route step by step. It combines population data, patient samples and several mouse models of oral squamous cell carcinoma, the most common form of mouth cancer.

From the brain to the bone marrow

In mice kept under chronic restraint stress, the researchers saw activity in a stress-control region of the hypothalamus. That activity led the pituitary gland to release more of a hormone called alpha-melanocyte-stimulating hormone (α-MSH). The hormone in turn drove the bone marrow to produce more of a type of immune cell called PMN-MDSCs, myeloid-derived suppressor cells. Despite being immune cells, they dampen the body's defences.

Inside tumours, a signalling molecule called CXCL13 helped draw these cells in. As they accumulated, fewer cancer-killing CD8 T cells reached the tumour, and nearby macrophages shifted toward a type that supports tumour growth. Stressed mice developed tumours faster and saw more cancer return after surgery. Neutralizing CXCL13 reversed much of the effect.

The team calls the circuit the hypothalamic-pituitary-bone marrow axis.

Signs of the same pattern in patients

The human evidence is smaller and correlational. In blood from 45 people (10 healthy, 15 with oral leukoplakia, a precancerous condition, and 20 with oral cancer), α-MSH levels and a marker of the suppressor cells rose in step from healthy to precancerous to cancerous. Tumour tissue from 143 oral cancer patients showed more suppressor cells at later stages. Patients whose tumours had more of them had fewer killer T cells and shorter survival.

The researchers also analysed the UK Biobank, a large health study following volunteers in Britain. They compared 1,477 people with head and neck squamous cell carcinoma against more than 384,000 cancer-free participants. People who screened positive for anxiety or depression on a short questionnaire had higher odds of the cancer and worse survival after adjusting for age, sex, smoking, alcohol use and income.

A possible add-on to immunotherapy

α-MSH acts through a family of receptors. When the team blocked one of them, the melanocortin 5 receptor (MC5R), with an experimental compound, and combined it with an anti-PD-1 immunotherapy drug, mice had the smallest tumours and the most T cells inside them of any group. The combination caused no obvious toxicity and reduced the weight loss seen with anti-PD-1 treatment alone. Checkpoint drugs like anti-PD-1 help only a minority of people with oral cancer, so a way to boost them would be significant.

The authors suggest that blood levels of α-MSH and of the suppressor cells could one day help identify patients at higher risk of progression or relapse. They also suggest routine screening for anxiety and depression could flag patients who need closer follow-up.

Caveats

The mechanism was worked out in mice, and the drug combination has not been tested in people. The authors also caution against over-reading the UK Biobank result. Anxiety and depression were measured only once, so the data cannot show which came first, and higher scores among cancer patients may partly reflect the distress of being diagnosed and treated. Depression is also linked to habits that independently worsen outcomes, such as poor oral hygiene, poor nutrition and missed treatment. The human blood samples involved only a few dozen people. The researchers say the pathway still needs to be confirmed in patients and tested in clinical trials.

Source: Yang, Z., Wang, T., Tian, X. et al., "Chronic stress drives tumorigenesis and progression via central nervous system-mediated neuroimmune circuits," International Journal of Oral Science (2026), doi:10.1038/s41368-026-00468-x.