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Though the therapeutic effect of GDF15 neutralizing antibody indicates a protumor role of secreted GDF15, the double\u2010edged effect of GDF15 has remained a mystery for a long. Herein, we performed single\u2010cell RNA\u2010sequencing on oral squamous cell carcinoma (OSCC) samples before and after ICB\u2010based therapy to explore the context\u2010dependent functions of GDF15 across distinct cellular subsets. It revealed that GDF15\n                    <jats:sup>+<\/jats:sup>\n                    macrophages were enriched in ICB\u2010sensitive OSCCs after treatment and might participate in mediating tumor regression.\n                    <jats:italic>Gdf15<\/jats:italic>\n                    <jats:sup>fl\/fl<\/jats:sup>\n                    <jats:italic>Lyz2<\/jats:italic>\n                    <jats:sup>Cre<\/jats:sup>\n                    mice illustrated that GDF15 deficiency in macrophages could accelerate tumor progression by suppressing the infiltration of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Mechanistically, macrophage\u2010intrinsic GDF15 could enhance the abilities to phagocyte tumor cells and to cross\u2010present antigens to CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. The functional enhancement of GDF15 was mediated through the upregulation of the NF\u2010\u03baB signaling pathway in macrophages. Collectively, the cellular source of GDF15 could determine its effect on tumor progression, with GDF15\n                    <jats:sup>+<\/jats:sup>\n                    macrophages exerting an antitumor role in OSCC, whereas secreted GDF15 exerting a protumor role. The latter could be neutralized by the GDF15 antibody. These findings would advance a comprehensive understanding of the double\u2010edged effect of GDF15.\n                  <\/jats:p>","DOI":"10.1002\/advs.202518525","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T18:52:03Z","timestamp":1773427923000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Context\u2010Dependent Role of GDF15: GDF15\n                    <sup>+<\/sup>\n                    Tumor\u2010Associated Macrophages Suppress OSCC Progression by Enhancing Phagocytosis"],"prefix":"10.1002","volume":"13","author":[{"given":"Xinyu","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Oral and Maxillofacial\u2010Head and Neck Oncology Ninth People's Hospital College of Stomatology Shanghai Jiao Tong University School of Medicine  Shanghai P. R. 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