Researchers at Vall d’Hebron found that blocking p38α improved anti-PD-1 treatment in melanoma models. The work also identified a nine-gene signature linked to treatment response and survival.
In experiments led by the Vall d’Hebron Instituto de Investigación, blocking p38α made melanoma tumours respond better to immunotherapy. The effect appeared when p38α inhibitors were combined with anti-PD-1 treatment. Used alone, the inhibitors did not produce the same result. Some animal models showed complete tumour elimination.
The finding points to a treatment-resistance mechanism that may be tackled with a combination therapy.
The immune effect involved both adaptive and innate components: removing p38α from tumour cells increased the activity of CD8+ T lymphocytes and natural killer cells, while also strengthening inflammatory signalling in the tumour environment.
The study was published in Nature Communications. It examines how p38α affects melanoma growth and the immune environment around the tumour.
Researchers from VHIR’s Biomedical Research Group in Melanoma worked with specialists from Vall d’Hebron University Hospital’s Dermatology and Pathology departments. The VHIR group focused on childhood cancer and haematological diseases also took part, along with VHIO, Cemcat, CNAG and PRBB.
An earlier regional report concerned a public event in Catalonia. This study concerns a laboratory finding that may have a future role in cancer treatment.
p38α does not act the same way at every stage of the disease. Before melanoma develops, the protein helps protect cells from damage caused by ultraviolet radiation. Once a tumour forms, p38α can support tumour growth. It can also help create conditions that weaken the immune response.
The findings support a treatment strategy in which p38α is targeted to reshape the tumour microenvironment while anti-PD-1 therapy activates the immune response. According to VHIR’s research context, this is a preclinical rationale for combination treatment, not evidence that p38α inhibition is ready for routine patient care.
The researchers removed p38α from tumour cells in animal models, human samples and cell cultures. CD8+ T lymphocytes and natural killer cells then became more active. Other signals linked to inflammation also grew stronger.
The tumours became more sensitive to anti-PD-1 therapy, which is already used against melanoma. The reason is simple.
p38α inhibitors alone did not reduce tumour size in the experiments. Combined with immunotherapy, they produced much better tumour control. Some animals reached complete tumour elimination.
VHIR researchers describe p38α as a possible target for overcoming resistance to immunotherapy. They say p38α inhibitors could make some less responsive tumours more vulnerable when used with anti-PD-1 treatment.
This is not yet a treatment option for patients. The findings need confirmation in more human samples. Further studies must also assess the safety and effectiveness of the combination in clinical trials.
That puts the work in therapeutic development, not routine medical care.
The study also points to a possible testing tool. Researchers identified a molecular signature made up of nine genes linked to p38α. Measuring the activity of those genes could help separate tumours that are more likely to respond to immunotherapy from tumours with a lower expected response.
The signature was also associated with better survival. For melanoma care, that creates two possible uses. p38α could become a target for combination treatment, while the nine-gene profile could help with patient selection.
The evidence links one biological mechanism with treatment sensitivity and survival. More confirmation is needed. Until clinical testing is complete, the discovery remains a strong research lead, not a ready-made answer to immunotherapy resistance.
