Vall d'Hebron researchers identified p38α as a possible target in melanoma treatment. Blocking the protein improved anti-PD-1 responses in experimental models and revealed a nine-gene signature linked to treatment outcomes.
Vall d'Hebron researchers found that blocking p38α made melanoma more sensitive to anti-PD-1 immunotherapy in experiments involving animal models, human samples and cell cultures. The findings were published in Nature Communications.
The discovery addresses a major problem in advanced melanoma: some tumours fail to respond to treatment initially, while others develop resistance later.
Removing p38α from tumour cells increased the activity of several immune system components. CD8+ T lymphocytes and natural killer cells became more active. Melanomas without the protein also responded better to anti-PD-1 treatment than tumours that retained p38α.
Around half of people with melanoma either fail to respond initially to PD-1/PD-L1 blockade or develop resistance later, information from a recent Bioengineer review. The review describes PD-1 blockade as an established part of melanoma care, while noting that many patients still need another way to overcome primary or acquired resistance. The FDA approved lifileucel in 2024 for patients with advanced melanoma that had not responded to PD-1/PD-L1 therapy.
The results point to a combination treatment rather than a standalone drug. The protein behaves differently at different stages of the disease: early in melanoma development, p38α helps protect cells from ultraviolet radiation damage. Once melanoma forms, the researchers found, it supports tumour growth and creates conditions that weaken the immune response.
This may explain why p38α has drawn attention as a treatment target. Removing the protein altered the tumour and strengthened the immune response against the cancer, helping anti-PD-1 therapy work better.
That result is consistent with the immunological explanation outlined in Frontiers in Immunology. Checkpoint inhibitors work by releasing inhibitory signals that hold back T-cell activity. Changing the tumour environment may strengthen that response.
The team then tested p38α inhibitors that have already been clinically validated. The drugs did not reduce tumour size when used alone in the models studied. Combined with immunotherapy, they produced stronger tumour control, and some animals lost their tumours completely.
Russpain described the finding as a preclinical combination strategy, not evidence that p38α inhibition can replace anti-PD-1 treatment. The data suggest that the drugs may help overcome resistance when given alongside anti-PD-1 treatment.
The study also offers a possible way to identify tumours more likely to respond. Researchers described a nine-gene molecular signature linked to p38α. The gene pattern distinguished tumours with a higher likelihood of responding to immunotherapy from those with a lower likelihood. It was also associated with longer survival.
The signature remains experimental. If later studies confirm it, doctors may be able to identify patients more likely to benefit from immunotherapy. The proposed drug combination also needs further testing.
Before either approach reaches patients, researchers must confirm the findings in human samples. Clinical trials must then assess the combination's safety and effectiveness.
New phase III studies discussed around ESMO 2026 are testing other ways to strengthen PD-1 blockade, including changes to MAPK signalling and the tumour environment. The p38α work follows that broader research direction but remains a preclinical result.
The research involved the Dermatology and Pathology Departments of Hospital Universitario Vall d'Hebron, the VHIR group focused on childhood cancer and haematological diseases, Vall d'Hebron Instituto de Oncología (VHIO), the Centro de Esclerosis Múltiple de Cataluña (Cemcat), the Centro Nacional de Análisis Genómico (CNAG) and the Parque de Investigación Biomédica de Barcelona (PRBB).
The study identifies two linked possibilities: making resistant melanoma more vulnerable to treatment and using a molecular profile to select patients more precisely. The strategy must still prove safe and effective in people.
