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.

Advances in the variations and biomedical applications of stimuli-responsive nanodrug delivery systems

“…Among other effects, PCP blocked PD-1/PD-L1 binding, thereby promoting the antitumor effects of T cells. Moreover, R848 induced the transformation of tumor-associated macrophages into M1-type macrophages and DOX promoted immunogenic cell death, thereby inducing a robust antitumor immune response [139] .…”

Amplifying “eat me signal” by immunogenic cell death for potentiating cancer immunotherapy

“…A tri‐functional delivery system consisting of doxorubicin, SAR405 (a highly specific VPS34 inhibitor) and anti‐PD‐L1 peptide JY4, potently up‐regulates the infiltration of CTLs through synergizing doxorubicin‐induced ICD and SAR405‐mediated release of chemokines (C‐C motif chemokine 5 (CCL5) and C‐X‐C ligand 10 (CXCL10)), ultimately inhibiting tumor growth, metastases, and resurrection through re‐education of the immunosuppressive tumor microenvironment 144 . PD‐1/PD‐L1 peptide antagonist PCP, doxorubicin and TLR7/8 agonist (R848) are co‐delivered through co‐assembling a multi‐agent prodrug, with specifical cleavage via fibroblast activation protein‐α (FAP‐α) within the tumor stromal region 145 . The localized release of doxorubicin and R848 evokes ICD and reprograms TAMs to elicit antitumor immune responses, while sustained release of PCP results in PD‐1/PD‐L1 blockades for subsequent propagated activation of CTLs.…”

Immunotherapy: cancer immunotherapy and its combination with nanomaterials and other therapies

“…Sun et al 191 investigated a novel nanotherapeutic platform. They designed an amphiphilic bifunctional PD-1/PD-L1 peptide antagonist PCP, and co-delivered DOX and R848 by co-assembling a multi-agent prodrug (PCP@R848/DOX) (Fig.…”