A Vall d'Hebron study points to p38a as a possible melanoma treatment target. Blocking the protein improved anti-PD-1 therapy in animal models, while a nine-gene profile may help identify tumours more likely to respond.
In Barcelona, researchers removed the p38a protein from melanoma cells and tested the change in animal models, human samples and cell cultures. The tumours became more exposed to immune attack. Some animals cleared the cancer completely.
The work came from the Vall d'Hebron Institut de Recerca. It suggests one possible way to overcome resistance to anti-PD-1 treatment. The approach has not been established as a patient therapy.
That distinction matters.
Alongside p38a, the researchers identified a nine-gene signature associated with the likelihood of responding to immunotherapy and with longer survival. It is a potential biomarker foundation, not yet a validated clinical test.
p38a has two different roles. Before melanoma develops, it helps protect cells from ultraviolet light and may stop them from becoming malignant. Once a tumour is established, the same protein supports its growth and helps create conditions that weaken the immune response.
The researchers found more CD8+ T lymphocytes and natural killer cells in tumours without p38a. The samples also showed stronger inflammation-related signals. That suggests p38a affects the tumour microenvironment, not only the melanoma cells themselves.
The reversal is the study's central finding.
The team then tested the link with anti-PD-1 therapy, one of the most widely used immunotherapies for melanoma. Tumours that retained p38a resisted the treatment. Tumours without the protein responded more readily.
The results offer a biological explanation for a familiar problem. Anti-PD-1 therapy controls some melanomas but fails against others.
The clinical problem is substantial: according to Replimune, roughly half of patients either do not respond to immune-checkpoint blockade or later experience progression. In the United States, an accelerated approval has also been granted for the next-generation T-VEC TUDRIQEV (vusolimogene oderparepvec) combined with nivolumab in adults with unresectable advanced cutaneous melanoma progressing after anti-PD-1 therapy; among 91 evaluable patients, the objective response rate was 24.2% and the median duration of response was 14.1 months.
Researchers also tested p38a inhibitors that have already been clinically validated. The drugs did not shrink tumours when used alone. With immunotherapy, they improved tumour control. In some animals, the combination eliminated the tumour.
These findings remain preclinical. Tumour clearance in some animals does not prove that the treatment works or is safe in people.
The study appeared in Nature Communications. It involved the Vall d'Hebron Hospital's Dermatology and Pathology departments, the Vhir group specialising in childhood cancer and haematological diseases, the Vall d'Hebron Instituto de Oncología, the Centro de Esclerosis Múltiple de Catalunya, the Centro Nacional de Análisis Genómico and the Parque de Investigación Biomédica de Barcelona.
The result sits within a wider biomedical research landscape that also includes earlier imaging research.
For melanoma treatment, the point is specific. p38a appears to shape the immune environment around the cancer, rather than merely tracking tumour behaviour. The study supports testing p38a inhibition alongside immunotherapy, not in place of it.
The evidence comes from animals, human samples and laboratory cultures. It does not establish a proven treatment for patients. Reports on the study also describe it as preclinical.
Still, the combination results make p38a a credible therapeutic target. They suggest that anti-PD-1 resistance may be attacked through the tumour's own protective mechanisms. The nine-gene signature could eventually help select patients for such treatment, but human clinical studies must validate it first.
