Removing p38a from melanoma cells made tumours easier for the immune system to attack. Researchers led by the Vall d'Hebron Institut de Recerca in Barcelona tested the approach alongside anti-PD-1 treatment. The combination produced the strongest results in animal models.
Published in Nature Communications, the study links p38a to resistance against one of the basic immunotherapies used for melanoma. Without the protein, immune activity rose 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 value in selecting patients still needs validation in independent clinical cohorts.
p38a has two distinct 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 stage of the study. The team removed p38a from melanoma cells in animal models, then examined human samples and cell cultures. The tumours showed increased activity from CD8+ T lymphocytes and natural killer cells, along with other inflammation-related signals. The findings suggest p38a affects both tumour cells and the tumour microenvironment, potentially making cancer easier for immune cells to reach.
The researchers also tested clinically validated p38a inhibitors. Used alone, the drugs did not reduce tumour size. Combined with anti-PD-1 treatment, they improved tumour control. Some animals had no detectable tumours afterward.
The outcome occurred in only some animals. The Nature Communications study reports complete tumour disappearance in a subset. These results do not establish the combination's effectiveness or safety in people.
The phrase “clinically validated inhibitors” refers to previous study of these compounds. It does not establish their effectiveness against melanoma when combined with anti-PD-1. The approach is not an established standard of care and needs testing in clinical trials.
The work involved the VHIR Biomedical Research Group in Melanoma, along with the Dermatology and Pathology Services of Hospital Universitari Vall d'Hebron. The VHIO Cancer and Hematological Diseases in Children group also took part, as did Cemcat, CNAG and the PRBB. Earlier coverage of related biomedical research in Spain describes the wider collaboration. A research summary from Vall d'Hebron places the findings within broader efforts 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. Researchers drew on laboratory cultures and animal models, as well as human samples. No patient results from a clinical trial are reported, and the study does not report that a trial of p38a inhibitors with anti-PD-1 has begun.
For melanoma research, the findings point to the tumour environment as part of the resistance problem. Changing that environment may help anti-PD-1 treatment work better. The inhibitors failed to shrink tumours on their own, 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 and study the p38a inhibitor with anti-PD-1 in clinical trials. The findings support further research, not routine care.
