Copper-Based Nanoparticle Co-Loaded with Natural PD-L1 Inhibitor and 5-Fluorouracil for Enhanced Immunotherapy of Hepatocellular Carcinoma

Despite the revolutionary breakthroughs in immunotherapy for hepatocellular carcinoma, its efficacy remains limited due to low tumor immunogenicity, insufficient immune cell infiltration, and an immunosuppressive tumor microenvironment. To address these challenges, we developed a novel copper-based nanoparticle designed for the synergistic delivery of the chemotherapeutic agent 5-fluorouracil (5-FU) and the natural programmed cell death ligand 1 (PD-L1) inhibitor chrysin (Chr). This nanosystem facilitates the targeted accumulation of these drugs at the tumor site and enables the responsive release of 5-FU, copper ions, and Chr in an acidic environment, thereby synergistically activating antitumor immune responses through the induction of cuproptosis, promotion of immunogenic cell death (ICD), and downregulation of PD-L1 expression. In vitro experiments demonstrated that this nanoparticle reduced the half-maximal inhibitory concentration (IC50) for Hepa1-6 cells by approximately 3.0 times compared with the administration of 5-FU alone. In vivo experiments revealed significant tumor suppression effects with an inhibition rate reaching as high as 89.8%. Notably, this nanoparticle successfully activated systemic antitumor immunity, as evidenced by a dendritic cell maturation rate of 32.9% in lymph nodes and a CD8+ T cell infiltration rate of 28.3% within the tumor microenvironment. This study presents an efficient nanomedicine strategy that synergistically induces cuprotosis and ICD and inhibits PD-L1 expression, thereby providing a new direction for enhancing immunotherapy in hepatocellular carcinoma.