Chimeric peptide-engineered photodynamic PD-L1 degrader for activating colorectal cancer immunity in combination with exosomal PD-L1 inhibition

The immunotherapy effect of colorectal cancer is severely compromised by the expression of programmed cell death ligand 1 (PD-L1) on tumor cells and exosomes. Herein, a chimeric peptide engineered photodynamic degrader (NPPM) is developed for colorectal cancer immunotherapy, combining photodynamic degradation of PD-L1 with inhibition of exosomal PD-L1 expression. Among these, NPPM integrates protoporphyrin IX (PpIX) with a PD-L1-targeting peptide sequence (CVRARTR), forming an amphiphilic chimeric peptide to load macitentan (MAC). NPPM demonstrates specific colorectal cancer targeting ability through PD-L1 recognition and generates substantial reactive oxygen species (ROS) upon light irradiation, thereby destroying tumor cells via photodynamic therapy (PDT). More interestingly, PDT not only triggers immunogenic cell death (ICD) to enhance tumor immunogenicity, but also induces PD-L1 degradation in tumor cells. Concurrently, the delivery of MAC synergistically decreases the expression of exosomal PD-L1, thus amplifying the immunotherapeutic effect. The synergistic functions of NPPM result in significant activation of systemic anti-tumor immunity, characterized by increased infiltration of T cells and reduced presence of regulatory T cells, effectively suppressing both primary and metastatic tumors. This study provides a new strategy to degrade the proteins of interest and also proposes a sophisticated mechanism to potentiate immunotherapy by overcoming multiple immunosuppressive factors.