Dual-Blockade Immune Checkpoint for Breast Cancer Treatment Based on a Tumor-Penetrating Peptide Assembling Nanoparticle

Abstract

Cancer immunotherapy can enhance the antitumor effect of drugs through a combinatorial approach in a synergistic manner. However, the effective targeted delivery of various drugs remains a challenge. We generated a peptide assembling tumor-targeted nanodelivery system based on a breast cancer homing and penetrating peptide for the codelivery of a programmed cell death ligand 1 (PD-L1) small interfering RNA (siRNA) (siPD-L1) and an indoleamine 2,3-dioxygenase inhibitor as a dual blockade of an immune checkpoint. The vector is capable of specifically accumulating in the breast cancer tumor site in a way that allows the siRNA to escape from endosomal vesicles after being endocytosed by tumor cells. The drug within these cells then acts to block tryptophan metabolism. The results showed that locally released siPD-L1 and 1-methyl-dl-tryptophan favor the survival and activation of cytotoxic T lymphocytes, resulting in apoptosis of breast cancer cells. Therefore, this study provides a potential approach for treating breast cancer by blocking immunological checkpoints through the assembly of micelles with functional peptides.