Coupling PD-L1 Inhibition and Lysosomal Degradation: Innovative Anti-PD-L1 Peptides for NSCLC Immunotherapy
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─<b>FM2</b> and <b>FM213</b>─emerged as promising bifunctional suppressors of PD-1/PD-L1 binding. Through a compound-centric proteomic approach, we demonstrated that <b>FM213</b> robustly binds to PD-L1 in NSCLC cells and exosomes. Furthermore, at its highest non-cytotoxic concentration (2 μM), <b>FM213</b> (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 <sup><b>D</b></sup><b>TBP-3</b>, a TIGIT inhibitor, and <b>FM213</b>, respectively, enhances the antitumor immunity of anti-PD-L1 ligands.
Authors
- Luciana Marinelli (ORCID: https://orcid.org/0000-0002-4084-8044)
- Francesco Sabbatino (ORCID: https://orcid.org/0000-0001-6431-8278)
- Łukasz Skalniak (ORCID: https://orcid.org/0000-0002-6707-6697)
- Giovanna Polcaro (ORCID: https://orcid.org/0000-0002-2329-3200)
- Simona Marzano (ORCID: https://orcid.org/0000-0002-6938-1687)
- Isidora Diakogiannaki
- Luigi Liguori (ORCID: https://orcid.org/0000-0002-0232-1452)
- Francesco Saverio Di Leva (ORCID: https://orcid.org/0000-0002-2294-0656)
- Francesco Merlino (ORCID: https://orcid.org/0000-0002-9607-229X)
- Pierfausto Seneci (ORCID: https://orcid.org/0000-0001-9709-7344)
- V. Mazzarella
- Pasquale Russomanno (ORCID: https://orcid.org/0000-0002-0236-1200)
- Greta Donati (ORCID: https://orcid.org/0000-0002-0311-1721)
- Salvatore Di Maro (ORCID: https://orcid.org/0000-0002-9286-4433)
- Jussara Amato (ORCID: https://orcid.org/0000-0001-6096-3544)
- Valentina Pagliara (ORCID: https://orcid.org/0000-0001-9320-6080)
- Stefano Pepe (ORCID: https://orcid.org/0000-0001-6280-8142)
- Ida Boccino (ORCID: https://orcid.org/0009-0002-6662-007X)
- Anella Saviano
- F Maione
- Diego Brancaccio
- Jacek Plewka
- Vincenzo Maria D’Amore
- Daniela Arosio
Institutions
- Jagiellonian University (PL)
- University of Milan (IT)
- University of Campania "Luigi Vanvitelli" (IT)
- Institute of Molecular Science and Technologies (IT)
- Ospedali Riuniti San Giovanni di Dio e Ruggi d'Aragona (IT)
- University of Naples Federico II (IT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-02-23
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02586
- Citations
- 1
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 24.20