Purinergic Receptor Nanoimmunoamplifiers Potentiate Chemoimmunotherapy Efficacy in Hepatocellular Carcinoma

The effectiveness of chemoimmunotherapy for hepatocellular carcinoma (HCC) is hindered by the weak immunogenicity of chemotherapy-induced immunogenic cell death (ICD). This limitation primarily stems from the insufficient activation of the extracellular adenosine triphosphate (eATP)/P2X7 purinergic receptor (P2X7R)/NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway in dendritic cells (DCs). To address this challenge, we designed ivermectin-MnO₂ nanocomplexes (IMNs) as P2X7R-targeted nanoimmunoamplifiers to enhance the immunogenicity of chemotherapy-induced ICD. The ivermectin component of IMN enhanced liposomal doxorubicin (LD)-induced ICD and increased P2X7R sensitivity to eATP. Additionally, the MnO₂ component of IMN alleviated tumor hypoxia and down-regulated CD39/CD73 expression, thereby preventing eATP degradation. These combined strategies robustly activated the eATP/P2X7R/NLRP3 inflammasome cascade in DCs, eliciting a potent antitumor immune response. In combination with anti-PD-L1 antibody and LD, IMN effectively inhibited tumor growth in orthotopic, subcutaneous, and metastatic HCC mouse models. Our study underscores the crucial role of IMN in amplifying the NLRP3 inflammasome cascade in DCs during ICD, presenting a promising strategy to enhance the efficacy of HCC chemoimmunotherapy.