A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy
Abstract The lysosome-targeting chimera (LYTAC) strategy provided a very powerful tool for the degradation of membrane proteins. However, the synthesis of LYTACs, antibody-small molecule conjugates, is challenging. The ability of antibody-based LYTACs to penetrate solid tumor is limited as well, esp...
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| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56648-6 |
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| Summary: | Abstract The lysosome-targeting chimera (LYTAC) strategy provided a very powerful tool for the degradation of membrane proteins. However, the synthesis of LYTACs, antibody-small molecule conjugates, is challenging. The ability of antibody-based LYTACs to penetrate solid tumor is limited as well, especially to cross the blood-brain barrier (BBB). Here, we propose a covalent chimeric peptide-based targeted degradation platform (Pep-TACs) by introducing a long flexible aryl sulfonyl fluoride group, which allows proximity-enabled cross-linking upon binding with the protein of interest. The Pep-TACs platform facilitates the degradation of target proteins through the mechanism of recycling transferrin receptor (TFRC)-mediated lysosomal targeted endocytosis. Biological experiments demonstrate that covalent Pep-TACs can significantly degrade the expression of PD-L1 on tumor cells, dendritic cells and macrophages, especially under acidic conditions, and markedly enhance the function of T cells and tumor phagocytosis by macrophages. Furthermore, both in anti-PD-1-responsive and -resistant tumor models, the Pep-TACs exert significant anti-tumor immune response. It is noteworthy that Pep-TACs can cross the BBB and prolong the survival of mice with in situ brain tumor. As a proof-of-concept, this study introduces a modular TFRC-based covalent peptide degradation platform for the degradation of membrane protein, and especially for the immunotherapy of brain tumors. |
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| ISSN: | 2041-1723 |