The impact of peptide surface density on PD-L1 receptor inhibition as a therapeutic strategy for triple negative breast cancer

Abstract

Immune checkpoint inhibitors (ICIs) disrupt receptor signaling, allowing the immune system to recognize and eliminate tumor cells across various cancers. ICI therapies have success in some cancers; however, most cancer patients do not show a therapeutic response. Antibodies, the current standard for ICIs, exhibit limited tumor penetration and immune-related side effects prompting the need for alternative strategies. Peptides are a promising alternative with the potential to overcome these limitations; however, their moderate binding affinity necessitates delivery platforms that enhance their therapeutic potential. Coupling peptides to nanoscale drug delivery systems such as liposomes has enhanced peptide binding affinity, selectivity and in vivo effectiveness. In this study, programmed cell death ligand 1 (PD-L1) antagonist peptides were conjugated to liposomes at varying surface densities to investigate the impact of density on tumor progression and immune cell infiltration. In vitro studies revealed that increasing the peptide density from 9000 peptides/μm² (1 mol%) to 53,000 peptides/μm² (3 mol%) enhanced binding extent, affinity, and rate. In contrast, in vivo studies showed that higher-density formulations had reduced tumor accumulation and no therapeutic effect, while the 24,000 peptides/μm² (1.5 mol%) formulation significantly inhibited tumor growth and promoted CD8⁺ T cell infiltration. These findings highlight the importance of optimizing ligand density for effective peptide-based ICI therapies.