Lipid droplet-loaded macrophages as a targetable pro-tumorigenic immune cell entity in human glioblastoma

Glioblastoma (GBM) presents a formidable clinical challenge due to its complex microenvironment. Here, we introduce tumor-associated foam cells (TAFs), a previously unidentified immune cell entity of lipid droplet (LD)-loaded macrophages, in GBM. Through extensive analyses of patient tumors, together with in vitro and in vivo investigations, we reveal that TAFs exhibit distinct pro-tumorigenic characteristics related to hypoxia, mesenchymal transition, angiogenesis, and impaired phagocytosis. Moreover, TAF presence correlates with worse patient outcome. Our mechanistic investigations demonstrate that TAF formation is facilitated by lipid cargo transfer from extracellular vesicles released by GBM cells. Importantly, we demonstrate that targeting key enzymes involved in LD formation, such as DGAT1 or ACSL, effectively disrupts TAF functionality. This study establishes TAFs as a prominent immune cell entity in GBM and provides valuable insights into their interplay within the microenvironment. Disrupting LD form