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.
In experiments with animal models, human samples and cell cultures, Vall d'Hebron researchers found that blocking p38α made melanoma more sensitive to anti-PD-1 immunotherapy. The work was published in Nature Communications.
The finding addresses a major problem in advanced melanoma. Some tumours fail to respond at the start. Others become resistant 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 still had p38α.
Around half of people with melanoma either do not respond initially to PD-1/PD-L1 blockade or later develop resistance, according to a recent Bioengineer review. This helps explain why combination strategies are a major focus of current research.
The results point to a combination treatment, not a standalone drug. Bioengineer described PD-1 blockade as an established part of melanoma care, but many patients still need another way to overcome primary or acquired resistance.
The protein behaves differently at different stages of the disease. Early in melanoma development, p38α helps protect cells from ultraviolet radiation damage. After melanoma forms, the researchers found that it supports tumour growth and creates conditions that make an immune response less effective.
That change matters.
It may explain why p38α has drawn attention as a treatment target. Removing the protein did more than alter the tumour itself. It also strengthened the immune response against the cancer, which helped anti-PD-1 therapy work better.
That result fits 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 make that response stronger.
Resistance to anti-PD-1 is already being addressed through several complementary strategies. The FDA approved lifileucel in 2024 for patients with advanced melanoma that had not responded to PD-1/PD-L1 therapy, underscoring the clinical importance of treatment-resistant disease.
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. With immunotherapy, they produced stronger tumour control. Some animals lost the tumour completely.
Russpain described the finding in the same way: a preclinical combination strategy, not proof that p38α inhibition can replace anti-PD-1 treatment.
The distinction matters. The data do not show that p38α inhibitors can replace immunotherapy. They 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 separated 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 safety and effectiveness of the combination.
New phase III studies discussed around ESMO 2026 are testing other ways to strengthen PD-1 blockade. Those approaches include changes to MAPK signalling and the tumour environment. The p38α work fits that wider research direction, but it 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 leaves researchers with two linked tools: a possible way to make resistant melanoma more vulnerable to treatment and a molecular profile for selecting patients more precisely. The next step is clear. The strategy must prove safe and effective in people.
