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Conventional systemic therapies such as sorafenib and its successors provide only modest survival benefits and are frequently complicated by toxicity and drug resistance. In recent years, immunotherapy has emerged as a promising avenue, yet its efficacy is often restricted by the profoundly immunosuppressive tumor microenvironment (TME). Within this landscape, exosomes\u2014nanoscale extracellular vesicles secreted by tumor, stromal, and immune cells\u2014have gained increasing attention for their central role in intercellular communication. They influence immune modulation, metabolic reprogramming, and therapeutic resistance, while also serving as potential biomarkers, nanocarriers, and vaccine platforms. Tumor\u2010derived exosomes (TEXs) contribute to immune evasion by suppressing CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, polarizing macrophages toward protumoral phenotypes, and enhancing immune checkpoint resistance. Conversely, engineered exosomes demonstrate significant therapeutic potential by reprogramming TAMs, improving drug delivery, and acting as cancer vaccines. Despite these advances, challenges remain in exosome biogenesis, heterogeneity, large\u2010scale production, and off\u2010target effects, which hinder clinical translation. Furthermore, interactions between exosomes and gut microbiota in modulating hepatic immunity represent an emerging frontier with unexplored therapeutic implications. Continued advances in bioengineering, nanotechnology, and systems biology are expected to refine exosome\u2010based therapies, offering novel, personalized strategies to improve outcomes for HCC patients.\n                  <\/jats:p>","DOI":"10.1111\/jgh.70245","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T11:31:09Z","timestamp":1770031869000},"page":"863-879","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Exosome\u2010Based Strategies in Hepatocellular Carcinoma: Mechanisms, Immunotherapy, and Clinical Challenges"],"prefix":"10.1111","volume":"41","author":[{"given":"Husni","family":"Farah","sequence":"first","affiliation":[{"name":"Faculty of Allied Medical Sciences, Hourani Center for Applied Scientific Research Al\u2010Ahliyya Amman University  Amman 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