PLIN2 Promotes Lipid Accumulation in Ascites‐Associated Macrophages and Ovarian Cancer Progression by HIF1α/SPP1 Signaling

Abstract A major characteristic of ovarian cancer (OC) is its unique route of metastasis via ascites. The immune microenvironment in ascites remains understudied, leaving the mechanism of ascites‐mediated abdominal metastasis obscure. Here, a single‐cell transcriptomic landscape of CD45⁺ immune cells across multiple anatomical sites is depicted, including primary tumors, metastatic lesions, and ascites, from patients diagnosed with high‐grade serous ovarian carcinoma (HGSOC). A novel subset of perilipin 2 high (PLIN2^hi) macrophages are identified that are enriched in ascites and positively correlated with OC progression, hence being designated as “ascites‐associated macrophages (AAMs)”. AAMs are lipid‐loaded with overexpression of the lipid droplet protein PLIN2. Overexpression or suppression of PLIN2 can enhance or inhibit tumor cell migration, invasion, and vascular permeability in vitro, which is also confirmed in vivo. Mechanistically, it is demonstrated that PLIN2 boosts HIF1α/SPP1 signaling in macrophages, thereby exerting pro‐tumor functions. Finally, a PLIN2‐targeting liposome is designed to efficiently suppress ascites production and tumor metastasis. Taken together, this work provides a comprehensive characterization of the cancer‐promoting function and lipid‐rich property of ascites‐enriched PLIN2^hi macrophages, establishes a link between lipid metabolism and hypoxia within the context of the ascites microenvironment, and elucidates the pivotal role of ascites in trans‐coelomic metastasis of OC.