In Barcelona, researchers removed the p38a protein from melanoma cells and tested the effects in animal models. They also examined human samples and cell cultures. The tumours became more exposed to immune attack, and some animals cleared the cancer completely.
The work came from the Vall d'Hebron Institut de Recerca. It points to one possible way to overcome resistance to anti-PD-1 treatment, although the approach has not been established as a patient therapy.
Alongside p38a, the researchers identified a nine-gene signature associated with the likelihood of responding to immunotherapy and with longer survival. It could form the basis for a biomarker, but it is 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, suggesting p38a affects the tumour microenvironment as well as the melanoma cells themselves.
This 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 treatment, while those 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. Information from Replimune, roughly half of patients either do not respond to immune-checkpoint blockade or later experience progression. In the United States, accelerated approval has also been granted for 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 on their own, but improved tumour control when combined with immunotherapy. In some animals, the combination eliminated the tumour.
These findings remain preclinical. Tumour clearance in some animals does not show 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 study is part of a wider biomedical research field that includes earlier imaging research.
For melanoma treatment, the finding 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 its place.
The evidence comes from animal models, human samples and laboratory cultures; it does not establish a proven treatment for patients. Reports on the study also describe it as preclinical.
The combination results make p38a a credible therapeutic target and suggest that anti-PD-1 resistance may be addressed 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.
