Exosome‐Based Strategies in Hepatocellular Carcinoma: Mechanisms, Immunotherapy, and Clinical Challenges

ABSTRACT Hepatocellular carcinoma (HCC) remains one of the most prevalent and lethal malignancies worldwide, characterized by late diagnosis, limited therapeutic options, and poor prognosis. 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—nanoscale extracellular vesicles secreted by tumor, stromal, and immune cells—have 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‐derived exosomes (TEXs) contribute to immune evasion by suppressing CD8 + 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‐scale production, and off‐target 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‐based therapies, offering novel, personalized strategies to improve outcomes for HCC patients.