Nanoplatforms revolutionizing hepatocellular carcinoma immunotherapy: From multimodal synergy to clinical application

Hepatocellular carcinoma (HCC), the most common primary liver cancer, remains a global health challenge due to its high recurrence rate, therapy resistance, and immunosuppressive tumor microenvironment (TME). Despite advancements in immune checkpoint inhibitors, clinical outcomes are limited by systemic toxicity and low response rates. Nanotechnology has emerged as a transformative approach to overcoming these barriers by enabling targeted delivery, multimodal synergy, and dynamic modulation of the TME. This review highlights the transformative potential of multifunctional nanoplatforms in revolutionizing HCC immunotherapy. These systems enable multimodal synergistic therapies, integrating chemoimmunotherapy, radio-immunotherapy, and ablation-immunotherapy, while dynamically remodeling the TME. We systematically examine nanoplatforms engineered to amplify immunogenic cell death (ICD), reprogram immunosuppressive cells such as tumor-associated macrophages (TAMs), and enhance the delivery and efficacy of immunotherapies. Beyond summarizing preclinical advances and clinical trials, we critically assess translational challenges, including biocompatibility and manufacturing scalability. Finally, we outline future directions such as AI-driven nanocarrier design, 4D-printed immune-modulatory scaffolds, and synthetic biology-based “living nanorobots,” pointing toward a new generation of smart, personalized nano-immunotherapies for HCC. • Multifunctional nanoplatforms overcome HCC immunosuppression via ICD and TME reprogramming. • Clinical-translational insights link preclinical advances to trials, tackling toxicity and poor response. • Future efforts focus on personalized nanomedicine to improve efficacy and minimize side effects.