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BACKGROUND & AIMS Extracellular vesicles (EVs) play a pivotal role in connecting tumor cells and their local and distant microenvironments. Here, we aimed to understand the role and molecular basis of patient-derived EVs in modulating cancer stemness and tumorigenesis in the context of hepatocellular carcinoma (HCC). METHODS EVs were isolated, quantified and characterized from patients' sera. The EVs were vigorously tested, both in vitro and in vivo, through various functional assays. Proteomic analysis was performed to identify the functional components of EVs. The presence and level of polymeric immunoglobulin receptor (pIgR) in circulating EVs and tumor and nontumorous tissues of HCC patients were determined by ELISA, immunoblotting, immunohistochemistry and quantitative PCR. The functional role and underlying mechanism of EVs with enhanced pIgR expression were elucidated. Blockade of EV-pIgR with neutralizing antibody was performed in nude mice implanted with patient-derived tumor xenografts (PDTXs). RESULTS Circulating EVs from late-stage HCC (L-HCC) patients had significantly elevated pIgR expression compared to the EVs released by control individuals. The augmenting effect of L-HCC-EVs on cancer stemness and tumorigenesis was hindered by anti-pIgR antibody. EVs enriched with pIgR consistently promoted cancer stemness and cancerous phenotypes in recipient cells. Mechanistically, EV-pIgR-induced cancer aggressiveness was abrogated by Akt and β-catenin inhibitors, confirming the role of EV-pIgR through activation of the PDK1/Akt/GSK3β/β-catenin signaling axis. Furthermore, an anti-pIgR neutralizing antibody attenuated tumor growth in mice implanted with PDTXs. CONCLUSIONS This study illustrates a previously unrevealed role of EV-pIgR in regulating cancer stemness and aggressiveness: EV-pIgR activates PDK1/Akt/GSK3β/β-catenin signaling cascades. The blockade of the intercellular communication mediated by EV-pIgR in the tumor microenvironment may provide a new therapeutic strategy for cancer patients. LAY SUMMARY Hepatocellular carcinoma (HCC) accounts for most primary liver cancers. The World Health Organization estimates that more than 1 million patients will die from liver cancer in 2030. Understanding the underlying mechanism by which HCC acquires aggressive attributes is crucial to improving the current methods for diagnosis and treatment of HCC patients. Herein, we demonstrated that nanometer-sized extracellular vesicles released by tumors in the sera of HCC patients promote cancer stemness and tumorigenesis. Within these oncogenic vesicles, we identified a key component that functions as a potent modulator of cancer aggressiveness. By inhibiting this functional component of EVs using a neutralizing antibody, tumor growth was profoundly attenuated in mice. The outcome of the study suggests an effective therapeutic alternative for cancer patients.