Extracellular vesicles as signal hubs and targeted platforms in hepatocellular carcinoma immunotherapy

Immunotherapy has transformed the management of hepatocellular carcinoma (HCC), yet its efficacy is frequently limited by the immunosuppressive tumor microenvironment (TME). Building on a systematic overview of current immunotherapeutic strategies, including immune checkpoint inhibitors, adoptive cell therapy, bispecific antibodies, therapeutic vaccines, and cytokines, we identify extracellular vesicles (EVs) as pivotal intercellular signaling hubs that underpin resistance across these diverse modalities. This review delineates the dual role of EVs in HCC immunotherapy, characterizing them as both central mediators of immune evasion and engineerable platforms for targeted therapy. We first synthesize how EVs orchestrate immunosuppressive signaling networks by shuttling immune checkpoint proteins, immunosuppressive protein effectors, regulatory non-coding RNAs, and metabolites to recipient immune and stromal cells, thereby establishing redundant and self-reinforcing suppressive circuits. These pathways drive T-cell exhaustion, M2 macrophage polarization, and expansion of immunosuppressive cell populations, collectively fostering a therapy-resistant niche. We then systematically examine two broad therapeutic strategies: directly targeting endogenous pathogenic EVs to intercept immunosuppressive signaling at its source, and engineering EVs as modular platforms capable of delivering nucleic acids, acting as Cytokine 2.0 platforms, serving as cell-free vaccines, or protecting oncolytic viruses. Furthermore, we highlight the emerging role of EV-based liquid biopsies, in which EV cargo reflects real-time TME dynamics and predicts responses to immunotherapy. Ultimately, this review underscores a paradigm shift; understanding and harnessing EV-mediated signaling is essential to overcoming resistance, while integrating EV-based diagnostics with engineered EV therapeutics paves the way for more precise and effective personalized immunotherapy in HCC. Tumor-derived extracellular vesicles suppress antitumor immunity via the PD-L1/PD-1 and CD73-adenosine pathways, while engineered vesicles deliver therapeutic cargoes to reinvigorate immune responses. Circulating EVs further serve as predictive biomarkers, highlighting their dual role as signal hubs and targeted platforms in hepatocellular carcinoma (HCC) immunotherapy.