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Treating ICB-resistant cancer by inhibiting PD-L1 via DHHC3 degradation induced by cell penetrating peptide-induced chimera conjugates

Shi, Yu-Ying, Fan, Gang, Tan, Ruirong, Li, Shan, Sun, Hua-Bing, Li, Rui, Yang, Mengni, Gao, Shanshan, Liu, Miao, Dai, Meng-Yuan·2024·Cell Death & Disease
DOI 10.1038/s41419-024-07073-yPMC PMC11442653

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Abstract

The current selection of ligands for both proteins of interest (POI) and E3 ubiquitin ligase significantly restricts the scope of targeted protein degradation (TPD) technologies. This study introduces cell-penetrating peptide-induced chimera conjugates (cp-PCCs) targeting the DHHC3 enzyme involved in PD-L1 palmitoylation. This approach disrupts PD-L1’s immunosuppressive function, enhancing anti-tumor immunity. We developed cp-PCCs to degrade DHHC3, directly linking DHHC3-mediated PD-L1 palmitoylation to PD-L1 stability on tumor cells. Our research utilized both in vitro assays and in vivo experiments in immune checkpoint blockade-resistant mouse models. We focused on a CRBN-based cp-PCC named PCC16, which demonstrated a DC50 of 102 nmol for DHHC3 degradation and significantly reduced PD-L1 levels. In resistant models, PCC16 not only robustly downregulated PD-L1 but also exhibited substantial anti-tumor activity in vivo without significant toxicity. This outperformed traditional inhibitors, showcasing the potential of cp-PCC technology to bypass current PROTAC limitations. Our findings suggest that cp-PCCs offer a promising method for targeting PD-L1 through DHHC3 inhibition and support their continued exploration as a versatile tool in cancer immunotherapy, especially for tumors resistant to standard treatments.

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Metadata

Authors
Shi, Y.-Y., Fan, G., Tan, R., Li, S., Sun, H.-B., Li, R., Yang, M., Gao, S., Liu, M., & Dai, M.-Y.
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2024-09-30
Volume
15
Issue
9
ISSN
2041-4889
DOI
10.1038/s41419-024-07073-y
PMC
PMC11442653
Cited by
28
References
4
Language
en
Update notices
correction (2024-11-18)
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