Nanodrug enhances post-ablation immunotherapy of hepatocellular carcinoma via promoting dendritic cell maturation and antigen presentation.

ABSTRACT

Thermal ablation (TA) as an effective method treating hepatocellular carcinoma (HCC) in clinics is facing great challenges of high recurrence and metastasis. Although immune-checkpoint blockade (ICB)-based immunotherapy has shown potential to inhibit recurrence and metastasis, the combination strategy of ICB and thermal ablation has shown little progress in HCC treatments. The tremendous hurdle for combining ICB with thermal ablation lies with the insufficient antigen internalization and immaturity of tumor-infiltrating dendritic cells (TIDCs) which leads to an inferior immune response to distant tumor growth and metastasis. Herein, an antigen-capturing nanoplatform, whose surface was modified with mannose as a targeting ligand, was constructed for co-delivering tumor-associated antigens (TAAs) and m6A demethylases inhibitor (i.e., fat mass and obesity associated gene (FTO) inhibitor) into TIDCs. In vivo results demonstrate that the intratumoral injection of nanodrug followed by HCC thermal ablation promotes dendritic cells (DCs) maturation, improves tumor infiltration of effector T cells and generates immune memory, which synergize with ICB treatment to inhibit the distant tumor growth and lung metastasis. Therefore, the antigen-capturing and FTO-inhibiting nanodrug holds potential to boost the ICB-based immunotherapy against HCC after thermal ablation.