Spiky metal-organic framework nanosystem for enhanced cuproptosis-mediated cancer immunotherapy

Immunotherapy, particularly αPD-1 therapy, has been hailed as a significant breakthrough in cancer treatment. However, the limited response rates and unknown mechanisms hinder the clinical application of αPD-1 blockade boosting with hybrid nanoparticles. Herein, we introduce a strategy to enhance cancer immunotherapy by leveraging cuproptosis, initiated by the spiky copper-based metal-organic framework (S@Cu-MOF) loaded with polyphyllin I (PPI) and synergized with αPD-1 therapy. Interestingly, the unique spiky structure of S@Cu-MOF not only significantly enhances tumor cell uptake but also leads to pronounced DNA damage. The application of S@Cu-MOF/PPI with αPD-1 therapy led to obvious tumor regression and prolonged survival due to cuproptosis, which involved substantial mitochondrial damage. This process amplifies the cGAS/STING immune pathway, enhancing the immune response against cancer. Additionally, this strategy promoted immunogenic cell death (ICD), recruitment of mature dendritic cells (DCs), T cell-mediated immunity, and effective memory CD8+ T cells, resulting in significant abscopal tumor suppression and lung metastasis reduction. Our study highlights the potential of S@Cu-MOF/PPI as a sensitizer for αPD-1 with the mechanism of cuproptosis and the cGAS/STING pathway, offering a promising strategy for the next generation of immunotherapy.