Chimeric\nPeptide-Engineered Polyprodrug Enhances Cytotoxic\nT Cell Response by Inducing Immunogenic Cell Death and Upregulating\nMajor Histocompatibility Complex Class I

Tumor-specific\ncytotoxic T cell immunity is critically dependent\non effective antigen presentation and sustained signal transduction.\nHowever, this immune response is frequently compromised by the inherently\nlow immunogenicity of breast cancer and the deficiency in major histocompatibility\ncomplex class I (MHC-I) expression. Herein, a chimeric peptide-engineered\nstoichiometric polyprodrug (PDPP) is fabricated to potentiate the\ncytotoxic T cell response, characterized by a high drug loading capacity\nand precise stoichiometric drug ratio, of which the immunogenic cell\ndeath (ICD) inducer of protoporphyrin IX (PpIX) and the epigenetic\ndrug of decitabine (DAC) are condensed into a polyprodrug called PpIX-DAC.\nFurthermore, programmed death ligand 1 (PD-L1) targeting peptide sequence\n(CVRARTR) is conjugated onto DSPE-PEG<sub>2000</sub>-Mal for encapsulation\nof PpIX-DAC, thereby enhancing breast cancer-targeted drug delivery.\nPDPP exerts its antitumor effects through photodynamic therapy (PDT),\nablating breast cancer cells while concurrently inducing the release\nof damage-associated molecular patterns (DAMPs) to boost tumor immunogenicity.\nAdditionally, PDPP can upregulate MHC-I expression <i>via</i> epigenetic modulation, synergistically augmenting the cytotoxic\nT cell response together with a PD-L1 blockade. In short, PDPP induces\na robust antitumor T cell immunity, causing effective eradication\nof primary and metastatic breast cancer. This study may inspire the\ndevelopment of stoichiometric nanomedicine for clinical translation.