{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:54:25Z","timestamp":1790963665153,"version":"4.1.0"},"reference-count":44,"publisher":"National Academy of Sciences","issue":"40","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32170725"],"award-info":[{"award-number":["32170725"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82003296"],"award-info":[{"award-number":["82003296"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:p>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2536086123","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:15:22Z","timestamp":1790961322000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["PAK4 exacerbates melanoma immunosuppression by promoting exosome release"],"prefix":"10.1073","volume":"123","author":[{"given":"Ruizhi","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Key Laboratory of Cell Biology, National Health Commission of China and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University","place":["Shenyang, 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