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-Ll 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. Statement of significance 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. We designed a glycyrrhetinic acid-based nanoplatform as a new ICD inducer (GCMNPs), with high cancer cell specificity and reduced toxicity to AML and CRC. GCMNPs cooperates with ferumoxytol to promote a Fenton reaction and induce ferroptosis. Moreover, the combination of GCMNPs and ferumoxytol enhanced the blockage of PD-1/PD-L1 to activate T cells, subsequently generating a systemic immune response in CRC and AML mouse models. This pre-clinical findings provide the proof-of-concept of combination of glycyrrhetinic acid-based nanomaterials and ferrotherapy as an ICD nano-inducer and immunotherapeutic agent for treating cancer. (C) 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Automated summary

Programmed cell death protein 1 (PD-1)/Programmed Cell Death Ligand 1 (PD-L1) blockade immunotherapy is limited by low response rates in many patients. This study developed a nanoplatform that induces immunogenic cell death and enhances tumor immunotherapy through synergistic effects with ferrotherapy. The combination of glycyrrhetinic acid-based nanomaterials and ferumoxytol improved T-cell immune response and showed potential for treating cancer.