Context‐Dependent Role of GDF15: GDF15 ⁺ Tumor‐Associated Macrophages Suppress OSCC Progression by Enhancing Phagocytosis

ABSTRACT The growth differentiation factor 15 (GDF15) neutralizing antibody has shown to overcome resistance to immune checkpoint blockade (ICB) in various solid tumors. Though the therapeutic effect of GDF15 neutralizing antibody indicates a protumor role of secreted GDF15, the double‐edged effect of GDF15 has remained a mystery for a long. Herein, we performed single‐cell RNA‐sequencing on oral squamous cell carcinoma (OSCC) samples before and after ICB‐based therapy to explore the context‐dependent functions of GDF15 across distinct cellular subsets. It revealed that GDF15 ⁺ macrophages were enriched in ICB‐sensitive OSCCs after treatment and might participate in mediating tumor regression. Gdf15 ^fl/fl Lyz2 ^Cre mice illustrated that GDF15 deficiency in macrophages could accelerate tumor progression by suppressing the infiltration of CD8 ⁺ T cells. Mechanistically, macrophage‐intrinsic GDF15 could enhance the abilities to phagocyte tumor cells and to cross‐present antigens to CD8 ⁺ T cells. The functional enhancement of GDF15 was mediated through the upregulation of the NF‐κB signaling pathway in macrophages. Collectively, the cellular source of GDF15 could determine its effect on tumor progression, with GDF15 ⁺ 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‐edged effect of GDF15.