Acoplamiento de la inhibición de PD-L1 y la degradación lisosómica: Péptidos anti-PD-L1 innovadores para la...

Antibodies targeting PD-1 and PD-L1 have achieved considerable success against various cancers, however their effectiveness is limited as both therapeutic and diagnostic tools. Meanwhile, small organic molecules and macrocyclic peptides are currently at various stages of development as modulators of the PD-1/PD-L1 axis. Here, we report an array of low molecular weight anti-PD-L1 macrocyclic peptides, among which two─FM2 and FM213─emerged as promising bifunctional suppressors of PD-1/PD-L1 binding. Through a compound-centric proteomic approach, we demonstrated that FM213 robustly binds to PD-L1 in NSCLC cells and exosomes. Furthermore, at its highest non-cytotoxic concentration (2 μM), FM213 (i) significantly enhances recognition and destruction of NSCLC cells by human PBMCs, and (ii) promotes the internalization of cell-surface PD-L1 into the cytosol, leading to its degradation via a lysosome-dependent pathway. Finally, coinhibition of TIGIT and PD-L1 by ^DTBP-3, a TIGIT inhibitor, and FM213, respectively, enhances the antitumor immunity of anti-PD-L1 ligands.