p38α Orchestrates BRAFV600E-Melanoma Progression and Immunotherapy Response via Tumor Fitness and Immune Microenvironment Modulation

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 MAPK-stress pathway, including upregulation of MAPK14.

We demonstrate a dual role for p38α in UVB-induced BrafV600E 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. Notably, loss or inhibition of p38α enhances and restores responsiveness to PD-1 blockade, leading to complete tumor regressions and increased overall survival, while a p38α-associated gene signature correlates with favorable immunotherapy outcomes in melanoma patients, underscoring its translational relevance.