• • NPPM achieves specific PD-L1 targeting via CVRARTR peptide, with photodynamic degradation of PD-L1 in tumor cells; this dual action addresses both surface and intracellular PD-L1, overcoming ICB resistance in colorectal cancer where response rates remain inconsistent and relapse occurs.
• • Upon light irradiation, NPPM generates substantial ROS, inducing ICD and enhancing tumor immunogenicity; this leads to increased T cell infiltration and reduced regulatory T cells, effectively suppressing primary and metastatic tumors in preclinical models.
• • Macitentan (MAC) delivery synergistically decreases exosomal PD-L1 expression, a critical factor in systemic immunosuppression; this combination amplifies the immunotherapeutic effect by targeting multiple immunosuppressive mechanisms simultaneously.
• • The chimeric peptide design integrates PpIX and PD-L1-targeting sequence, forming an amphiphilic structure that loads MAC; this engineering approach enables precise protein degradation and offers a universal strategy for targeting proteins of interest, with potential for clinical translation in colorectal cancer immunotherapy.