Chimeric Peptide-Engineered Photodynamic PD-L1 Degrader for Activating Colorectal Cancer Immunity in Combination with Exosomal PD-L1 Inhibition
Colorectal cancer immunotherapy is severely compromised by programmed cell death ligand 1 (PD-L1) expression on tumor cells and exosomes. This study develops a chimeric peptide-engineered photodynamic degrader (NPPM) that integrates protoporphyrin IX (PpIX) with a PD-L1-targeting peptide sequence (CVRARTR) to form an amphiphilic chimeric peptide loading macitentan (MAC). NPPM specifically targets colorectal cancer via PD-L1 recognition and generates substantial reactive oxygen species (ROS) upon light irradiation, destroying tumor cells through photodynamic therapy (PDT). PDT triggers immunogenic cell death (ICD) to enhance tumor immunogenicity and induces PD-L1 degradation in tumor cells. Concurrently, MAC delivery synergistically decreases exosomal PD-L1 expression, amplifying immunotherapeutic effect. The synergistic functions of NPPM result in significant activation of systemic anti-tumor immunity, characterized by increased T cell infiltration and reduced regulatory T cells, effectively suppressing both primary and metastatic tumors. This study provides a new strategy to degrade proteins of interest and proposes a sophisticated mechanism to potentiate immunotherapy by overcoming multiple immunosuppressive factors.