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Peer-reviewedCC BY-NC-NDNature communications

p38α orchestrates BRAFV600E-melanoma progression and immunotherapy response via tumor fitness and immune microenvironment modulation.

  • Paula Granado-Martínez1
  • Kimberley McGrail1
  • Roberto Orsenigo1
  • Ginevra Caratù2
  • Paula Nieto2
  • Yuxin Ding1
  • Ángel Nebreda3,4
  • Juan Martín-Caballero5,6
  • Iván Ortega5,7
  • Herena Eixarch8
  • Carmen Espejo8
  • Adrià Molero-Valenzuela9
6 more authors
  • Javier Hernandez-Losa10
  • Berta Ferrer1,10
  • Holger Heyn2,4,11
  • Eva Muñoz-Couselo12
  • Vicenç García-Patos1,13
  • Juan A Recio14
14 affiliations
  1. 1Biomedical Research in Melanoma-Animal Models and Cancer Laboratory-Vall d´Hebron Research Institute VHIR-Vall d'Hebron Hospital-UAB, Instituto de Investigación Sanitaria Hospital Universitari Vall d'Hebron (IIS IR-HUVH), Barcelona, Spain.
  2. 2Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain.
  3. 3Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona, Spain.
  4. 4Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, Barcelona, Spain.
  5. 5Animal Laboratory Unit; Biomedical Research Park of Barcelona-PRBB, Barcelona, Spain.
  6. 6Independent researcher, Madrid, Spain.
  7. 7University of Barcelona, Bellvitge, Spain.
  8. 8Neurology Department, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Vall d´Hebron Research Institute VHIR-Vall d'Hebron Hospital-UAB, Instituto de Investigación Sanitaria Hospital Universitari Vall d'Hebron (IIS IR-HUVH), Barcelona, 08035, Spain.
  9. 9Childhood Cancer and Blood Disorders Group, Vall d´Hebron Research Institute VHIR-Vall d'Hebron Hospital-UAB, Instituto de Investigación Sanitaria Hospital Universitari Vall d'Hebron (IIS IR-HUVH), Barcelona, 08035, Spain.
  10. 10Anatomy Pathology Department, Vall d'Hebron Hospital-UAB, Barcelona, Spain.
  11. 11Universitat de Barcelona, Barcelona, Spain.
  12. 12Vall d'Hebron Institute of Oncology VHIO-Vall d'Hebron Hospital-UAB, Instituto de Investigación Sanitaria Hospital Universitari Vall d'Hebron (IIS IR-HUVH), Barcelona, Spain.
  13. 13Dermatology Department, Vall d'Hebron Hospital-UAB, Barcelona, Spain.
  14. 14Biomedical Research in Melanoma-Animal Models and Cancer Laboratory-Vall d´Hebron Research Institute VHIR-Vall d'Hebron Hospital-UAB, Instituto de Investigación Sanitaria Hospital Universitari Vall d'Hebron (IIS IR-HUVH), Barcelona, Spain. [email protected].
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Abstract

Understanding how tumor cells shape the tumor microenvironment (TME) and evade the host immune response is critical for developing novel therapeutic combinations. In this study, we identify tumor cell p38α as a therapeutic target that restricts antitumor immunity and contributes to resistance against immune-checkpoint inhibitors (ICIs). Genetic analyses of mouse and human melanomas reveal alterations in the mitogen-activated protein kinase (MAPK)-stress pathway, including upregulation of MAPK14. We demonstrate a dual role for p38α in ultraviolet-B (UVB)-induced Braf V600E melanoma, acting as a tumor suppressor during melanocyte transformation but promoting melanoma growth and progression. Mechanistically, p38α impairs cytotoxic immune responses, modulates immunosuppressive myeloid cells, and regulates inflammatory mediators that shape the TME. Loss or inhibition of p38α enhances and restores sensitivity to PD-1 blockade, resulting in tumor regression and improved overall survival. Moreover, a p38α-associated gene signature correlates with favorable immunotherapy outcomes in patients with melanoma, underscoring its translational relevance.

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Cite

BibTeXRIS
BibTeX
@article{granadomartinez2026p38α,
  title = {{p38α orchestrates BRAFV600E-melanoma progression and immunotherapy response via tumor fitness and immune microenvironment modulation.}},
  author = {Paula Granado-Martínez and Kimberley McGrail and Roberto Orsenigo and Ginevra Caratù and Paula Nieto and Yuxin Ding and Ángel Nebreda and Juan Martín-Caballero and Iván Ortega and Herena Eixarch and Carmen Espejo and Adrià Molero-Valenzuela and Javier Hernandez-Losa and Berta Ferrer and Holger Heyn and Eva Muñoz-Couselo and Vicenç García-Patos and Juan A Recio},
  journal = {Nature communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-77868-4},
  url = {https://europepmc.org/article/MED/42907443},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - p38α orchestrates BRAFV600E-melanoma progression and immunotherapy response via tumor fitness and immune microenvironment modulation.
AU  - Paula Granado-Martínez
AU  - Kimberley McGrail
AU  - Roberto Orsenigo
AU  - Ginevra Caratù
AU  - Paula Nieto
AU  - Yuxin Ding
AU  - Ángel Nebreda
AU  - Juan Martín-Caballero
AU  - Iván Ortega
AU  - Herena Eixarch
AU  - Carmen Espejo
AU  - Adrià Molero-Valenzuela
AU  - Javier Hernandez-Losa
AU  - Berta Ferrer
AU  - Holger Heyn
AU  - Eva Muñoz-Couselo
AU  - Vicenç García-Patos
AU  - Juan A Recio
PY  - 2026
DA  - 2026/09/22
JO  - Nature communications
DO  - 10.1038/s41467-026-77868-4
UR  - https://europepmc.org/article/MED/42907443
AB  - Understanding how tumor cells shape the tumor microenvironment (TME) and evade the host immune response is critical for developing novel therapeutic combinations. In this study, we identify tumor cell p38α as a therapeutic target that restricts antitumor immunity and contributes to resistance against immune-checkpoint inhibitors (ICIs). Genetic analyses of mouse and human melanomas reveal alterations in the mitogen-activated protein kinase (MAPK)-stress pathway, including upregulation of MAPK14. We demonstrate a dual role for p38α in ultraviolet-B (UVB)-induced Braf V600E melanoma, acting as a tumor suppressor during melanocyte transformation but promoting melanoma growth and progression. Mechanistically, p38α impairs cytotoxic immune responses, modulates immunosuppressive myeloid cells, and regulates inflammatory mediators that shape the TME. Loss or inhibition of p38α enhances and restores sensitivity to PD-1 blockade, resulting in tumor regression and improved overall survival. Moreover, a p38α-associated gene signature correlates with favorable immunotherapy outcomes in patients with melanoma, underscoring its translational relevance.
SN  - 2041-1723
ER  -