Extracellular vesicles from ovarian cancer cells induce senescent lipid-laden macrophages to facilitate omental metastasis

作者：Guoqing Li, Xiaoling Zhou, Wenhan Li, Qiulei Wu, Ying Liu, Lin Huang, Xiaoli Liu, Jing Zhao, Xiangyu Xu, Linjuan Xu, Zehua Wang, Lanqing Gong, Liqiong Cai, Jing Cai · 发表于：Journal of Nanobiotechnology · 年份：2025 · DOI：10.1186/s12951-025-03612-7 · 被引用次数：5 · 研究领域：Extracellular vesicles in disease、Immune cells in cancer、Cancer Cells and Metastasis

BACKGROUND: Ovarian cancer exhibits striking metastatic tropism for the omentum, where lipid-laden macrophages are key mediators that fuel disease progression. However, the mechanisms governing their formation and pro-metastatic functions remain poorly understood. As extracellular vesicles (EVs) have as critical regulators of tumor-stroma crosstalk in metastatic niches, we sought to define how ovarian cancer-derived EVs orchestrate macrophages and adipocytes, and their impact on omental metastasis, aiming to explore potential therapeutic interventions. RESULTS: Single-cell transcriptomics of ovarian cancer revealed a distinct lipid-laden macrophage population in omentum, whose abundance correlated with metastatic burden and poor survival. Proteomics revealed that EVs from highly metastatic ovarian cancer cells were enriched in lipid metabolism regulators. In vivo experiments demonstrated that these tumor-derived vesicles mediated macrophage reprogramming, driving the acquisition of a pro-metastatic phenotype. Quantitative lipidomic profiling and lipid staining approaches confirmed the progressive lipid-laden in EV-treated macrophages. Using a patient-derived omentum-macrophage co-culture system, we demonstrated that tumor-derived EVs stimulate lipid release from omental adipocytes, which macrophages subsequently internalize through CD36-dependent uptake to drive lipid accumulation. This metabolic reprogramming culminated in cellular senescence, as evidenced by classical bioma...