Chimeric Peptide-Engineered Polyprodrug Enhances Cytotoxic T Cell Response by Inducing Immunogenic Cell Death and Upregulating Major Histocompatibility Complex Class I

Abstract

Tumor-specific cytotoxic T cell immunity is critically dependent on effective antigen presentation and sustained signal transduction. However, this immune response is frequently compromised by the inherently low immunogenicity of breast cancer and the deficiency in major histocompatibility complex class I (MHC-I) expression. Herein, a chimeric peptide-engineered stoichiometric polyprodrug (PDPP) is fabricated to potentiate the cytotoxic T cell response, characterized by a high drug loading capacity and precise stoichiometric drug ratio, of which the immunogenic cell death (ICD) inducer of protoporphyrin IX (PpIX) and the epigenetic drug of decitabine (DAC) are condensed into a polyprodrug called PpIX-DAC. Furthermore, programmed death ligand 1 (PD-L1) targeting peptide sequence (CVRARTR) is conjugated onto DSPE-PEG₂₀₀₀-Mal for encapsulation of PpIX-DAC, thereby enhancing breast cancer-targeted drug delivery. PDPP exerts its antitumor effects through photodynamic therapy (PDT), ablating breast cancer cells while concurrently inducing the release of damage-associated molecular patterns (DAMPs) to boost tumor immunogenicity. Additionally, PDPP can upregulate MHC-I expression via epigenetic modulation, synergistically augmenting the cytotoxic T cell response together with a PD-L1 blockade. In short, PDPP induces a robust antitumor T cell immunity, causing effective eradication of primary and metastatic breast cancer. This study may inspire the development of stoichiometric nanomedicine for clinical translation.