PAK4 exacerbates melanoma immunosuppression by promoting exosome release
Menée à l'aide de lignées cellulaires de mélanome, d'échantillons tumoraux de patients et de xénogreffes sur des modèles murins, cette étude met en évidence un mécanisme par lequel la kinase PAK4 accroît l'immunosuppression en favorisant la sécrétion, par les cellules cancéreuses, d'exosomes enrichis en PD-L1 qui réduisent le nombre et la fonction des lymphocytes T CD8+
Melanoma remains a lethal malignancy with frequent resistance to immune checkpoint blockade therapy. Clinical evidence associates elevated PAK4 expression with poor response to anti-PD-1 treatment in melanoma patients. While tumor-derived exosomes are recognized as key immunosuppressive mediators, the role of PAK4 in regulating exosome secretion to induce immunosuppression remains incompletely understood. Here, we demonstrate that PAK4-mediated phosphorylation of Annexin-A2 (ANXA2) at Ser26 promotes its nuclear-to-cytoplasmic translocation, facilitating the formation of S100A10-ANXA2 heterotetramers that drive multivesicular body docking to the plasma membrane. Furthermore, PAK4 stabilizes synaptotagmin-1 by suppressing Trim21-mediated ubiquitin degradation, enabling SNARE complex assembly for membrane fusion. PAK4-driven exosomes exhibit potent immunosuppressive activity, substantially reducing CD8+ T cell numbers and impairing their function in mouse models. Notably, melanoma cells with high PAK4 expression secrete PD-L1-enriched exosomes that promote systemic immune evasion. In patient-derived xenograft models, pharmacological inhibition of PAK4 attenuates tumor progression and reduces circulating exosomal PD-L1 levels. Our study unveils a dual mechanism through which PAK4 drives exosome-dependent immunosuppression, providing a rationale for combining PAK4 pathway inhibitors with immune checkpoint blockade and offering translational strategies to overcome melanoma immunotherapy resistance.
Proceedings of the National Academy of Sciences , résumé, 2026