Researchers in Barcelona identified p38a as a possible target in melanoma. Blocking the protein strengthened anti-PD-1 treatment in animal models and sometimes cleared tumours completely, but the findings remain preclinical.
In melanoma cells, removing p38a made tumours easier for the immune system to attack. Researchers led by the Vall d'Hebron Institut de Recerca in Barcelona tested the approach with anti-PD-1 treatment. The combination produced the strongest results in animal models.
The study was published in Nature Communications. It links p38a to resistance against one of the main immunotherapies used for melanoma. Without the protein, immune activity increased and tumour control improved.
The researchers also identified a nine-gene signature associated with p38α activity, the likelihood of responding to immunotherapy and longer survival. Its usefulness for selecting patients still requires validation in independent clinical cohorts.
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 helps it grow and limits the body's antitumour defence.
That reversal shaped the next part of the study. The team removed p38a from melanoma cells in animal models, human samples and cell cultures. The tumours then showed more activity from CD8+ T lymphocytes, natural killer cells and other inflammation-related signals. The results suggest that p38a affects tumour cells and the tumour microenvironment. It may make the cancer easier for immune cells to reach.
The researchers also tested clinically validated p38a inhibitors. The drugs did not reduce tumour size when used alone. Combined with anti-PD-1 treatment, they improved tumour control. Some animals had no detectable tumours afterward.
That happened only in some animals.
As described in the Nature Communications study, complete tumour disappearance occurred in a subset of animals. The results do not establish the combination's effectiveness or safety in people.
The phrase "clinically validated inhibitors" refers to previous experience studying these compounds; it does not show that they are effective against melanoma when combined with anti-PD-1. The approach is not an established standard of care for patients and requires testing in clinical trials.
The work involved the VHIR Biomedical Research Group in Melanoma, the Dermatology and Pathology Services of Hospital Universitari Vall d'Hebron, the VHIO Cancer and Hematological Diseases in Children group, Cemcat, CNAG and the PRBB. Earlier research coverage on related biomedical work in Spain describes the wider collaboration. A research summary from Vall d'Hebron places the findings within a broader effort to understand why some tumours respond poorly to immune-based treatment.
The study does not establish a new treatment for patients. It shows that blocking p38a may improve an existing immunotherapy under the experimental conditions tested. The evidence came from laboratory cultures, animal models and human samples. No reported clinical trial produced patient results, and the available materials do not indicate that a trial of the p38a inhibitor with anti-PD-1 has begun.
For melanoma research, the result points to the tumour environment as part of the resistance problem. Changing that environment may help anti-PD-1 treatment work better. The inhibitors alone failed to shrink tumours, so the proposed approach depends on the combination.
Further work has two clear tasks. Researchers need to test the nine-gene signature in independent clinical cohorts. They also need to study the p38a inhibitor and anti-PD-1 combination in clinical trials. The findings support more research, not routine care. They identify a specific biological barrier and a way to test it.
