POSTN ⁺ CAF-Derived Migrasomes Drive Hepatocellular Carcinoma Progression and Confer Resistance to Immunotherapy

Cancer-associated fibroblasts (CAFs) are known to shape the tumor microenvironment, yet the role of extracellular vesicles they produce, particularly migrasomes, in hepatocellular carcinoma (HCC) remains largely unexplored. In this study, we identified a subset of POSTN⁺ CAFs as the main source of migrasomes in HCC, predominantly located at the tumor-stroma interface. Transcriptomic data from TCGA and ICGC were used to compute a Migrasome_Score via GSVA, revealing strong associations with poor prognosis and immune checkpoint blockade resistance across cancers. Mechanistically, POSTN⁺ CAF-derived migrasomes enhanced endothelial angiogenic activity by delivering VEGFA and activating the VEGFR2-PI3K-AKT-eNOS pathway, promoting vascular remodeling within tumors. Migrasomes also induced malignant reprogramming of nearby hepatocytes by boosting oxidative phosphorylation and reactive oxygen species (ROS) production, leading to DNA damage and oncogenic transformation-effects reversed by ROS scavenging. Additionally, POSTN⁺ CAFs and their migrasomes physically hindered immune cell infiltration, forming a barrier that shielded tumor cells from immune surveillance. Together, these findings identify POSTN⁺ CAF-derived migrasomes as key drivers of HCC progression by promoting angiogenesis, malignant transformation, and immune exclusion. Their strong links to poor prognosis and immunotherapy resistance suggest that they may serve as promising therapeutic targets and prognostic biomarkers in HCC and beyond.