Fibroblast Activation Protein-α Responsive Peptide Assembling Prodrug Nanoparticles for Remodeling the Immunosuppressive Microenvironment and Boosting Cancer Immunotherapy.

Abstract

Checkpoint blockade immunotherapy has broad application prospects in the clinical treatment of malignant tumors. However, the low response rate of the checkpoint blockade is due to low tumor immunogenicity and immunosuppression within the tumor microenvironment. Herein, the authors design an amphiphilic bifunctional PD-1/PD-L1 peptide antagonist PCP, and co-deliver doxorubicin (DOX) and R848 through co-assembly of a multi-agent prodrug (PCP@R848/DOX), which can be specifically cleaved by fibroblast activation protein-α (FAP-α) in the tumor stroma. Upon reaching the tumor tissue, the PCP@R848/DOX prodrug nanostructure is disassembled by FAP-α. The localized release of DOX and R848 triggers immunogenic cell death (ICD) and reprograms tumor-associated macrophages (TAMs) to elicit antitumor immunity. Furthermore, sustained release of PD-1 or PD-L1 peptide antagonists mediates the PD-L1 pathway blockade for further propagated activation of cytotoxic T lymphocytes. Notably, a tumor microenvironment activatable prodrug nanoparticle is presented for triple-modality cancer therapy that functions by simultaneously activating ICD and altering the phenotype of TAMs when combined with PD-1 blockade therapy, which efficiently elicits a strong systemic antitumor immune response. This strategy may emerge as a new paradigm in the treatment of cancer by combination immunotherapy.

• Authors: Mengqi Sun, Shaobo Yao, Linyang Fan, Zhiguo Fang, Weibing Miao, Zhiyuan Hu, Zihua Wang
• Journal: Small (Weinheim an der Bergstrasse, Germany) (Small) Vol. 18 Issue 9 Pg. e2106296 (03 2022) ISSN: 1613-6829 [Electronic] Germany
• PMID: 34914185 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 Wiley-VCH GmbH.

Chemical References

• Membrane Proteins
• Peptides
• Prodrugs
• Endopeptidases
• fibroblast activation protein alpha

Topics

• Cell Line, Tumor
• Endopeptidases
• Immunotherapy
• Membrane Proteins
• Nanoparticles (chemistry)
• Neoplasms
• Peptides
• Prodrugs (pharmacology)
• Tumor Microenvironment