A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy

Youmei Xiao, Zhuoying He, Wanqiong Li, Danhong Chen, Xiaoshuang Niu, Xin Yang, Wenxuan Zeng, Mengfan Wang, Yuzhen Qian, Ye Su, Feiyu Luo, Guanyu Chen, Juan Liu, Xinghua Sui, Xiuman Zhou () and Yanfeng Gao ()
Additional contact information
Youmei Xiao: Shenzhen Campus of Sun Yat-sen University
Zhuoying He: Shenzhen Campus of Sun Yat-sen University
Wanqiong Li: Sun Yat-sen University
Danhong Chen: Shenzhen Campus of Sun Yat-sen University
Xiaoshuang Niu: Shenzhen Campus of Sun Yat-sen University
Xin Yang: Shenzhen Campus of Sun Yat-sen University
Wenxuan Zeng: Shenzhen Campus of Sun Yat-sen University
Mengfan Wang: Shenzhen Campus of Sun Yat-sen University
Yuzhen Qian: Zhengzhou University
Ye Su: Shenzhen Campus of Sun Yat-sen University
Feiyu Luo: Shenzhen Campus of Sun Yat-sen University
Guanyu Chen: Shenzhen Campus of Sun Yat-sen University
Juan Liu: Shenzhen Campus of Sun Yat-sen University
Xinghua Sui: Shenzhen Campus of Sun Yat-sen University
Xiuman Zhou: Shenzhen Campus of Sun Yat-sen University
Yanfeng Gao: Shenzhen Campus of Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-56648-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56648-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-56648-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().