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

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.