Glycyrrhetinic acid nanoparticles combined with ferrotherapy for improved cancer immunotherapy

Programmed cell death protein 1 (PD-1)/Programmed Cell Death Ligand 1 (PD-L1) blockade immunotherapy has emerged as a promising strategy to treat both solid and hematological malignancies. Despite the considerable therapeutic effects obtained in pre-clinical and clinical studies, PD-1/PD-L1 blockade therapy is still limited by the low benefit rates and a large number of patients still do not respond to this treatment. In this study, we developed a highly efficient and cancer-specific immunogenic cell death nanoinducer for effective tumor immunotherapy. A leukocyte membrane coated poly (lactic-co-glycolic acid) encapsulating glycyrrhetinic acid (GCMNPs) was developed to enhance targeting, tumor-homing capacity, and reduce toxicity in vivo. GCMNPs could induce ferroptosis in acute myeloid leukemia and colorectal cancer cells by downregulating glutathione-dependent peroxidases 4, leading to increased lipid peroxidation levels. Moreover, GCMNPs and ferumoxytol could synergistically enhance Fe-dependent cytotoxicity through the Fenton reaction. Finally, in vivo studies showed that GCMNPs synergized with ferumoxytol and anti-PD-L1 synergistically improve T-cell immune response against leukemia and colorectal tumor. This study anticipated that the combination of glycyrrhetinic acid-based nanomaterials and ferrotherapy would provide further insights into anti-cancer immune response to PD-1/PD-L1 blockade for both solid and hematological malignancies.