Coupling PD-L1 Inhibition and Lysosomal Degradation: Innovative Anti-PD-L1 Peptides for NSCLC Immunotherapy

Area of Science:

• Immunology
• Oncology
• Drug Discovery

Background:

• Antibodies targeting PD-1/PD-L1 are successful cancer therapies but have limitations.
• Small molecules and macrocyclic peptides are emerging as PD-1/PD-L1 axis modulators.

Purpose of the Study:

• To develop novel low molecular weight macrocyclic peptides targeting PD-L1.
• To evaluate the bifunctional suppressive capabilities of these peptides on PD-1/PD-L1 binding.
• To assess the therapeutic potential of FM213 in non-small cell lung cancer (NSCLC).

Main Methods:

• Compound-centric proteomic analysis to confirm FM213 binding to PD-L1 in NSCLC cells and exosomes.
• Assessment of FM213's effect on NSCLC cell recognition and destruction by human peripheral blood mononuclear cells (PBMCs).
• Investigation of PD-L1 internalization and degradation pathways induced by FM213.

Main Results:

• FM213 robustly binds to PD-L1 on NSCLC cells and exosomes.
• FM213 enhances PBMC-mediated killing of NSCLC cells at non-cytotoxic concentrations.
• FM213 induces lysosome-dependent degradation of cell-surface PD-L1.
• Combination therapy with a TIGIT inhibitor (DTBP-3) and FM213 amplifies antitumor immunity.

Conclusions:

• FM213 is a promising bifunctional suppressor of PD-1/PD-L1 binding with therapeutic potential in NSCLC.
• FM213 enhances anti-tumor immunity by promoting PD-L1 degradation and enabling combination therapies.
• Targeting PD-L1 with macrocyclic peptides offers a viable alternative to antibody-based therapies.