PXD058523

PXD058523 is an original dataset announced via ProteomeXchange.

Title	Development of polyvalent folate receptor-targeting chimeras (FRTACs) for lysosomal degradation of membrane proteins
Description	Lysosome-targeting chimeras (LYTACs) have emerged as a revolutionary targeted protein degradation (TPD) technology in modulating the levels of extracellular and membrane proteins. However, lack of lysosome-trafficking receptors (LTRs) limits the development of LYTACs. Here, we firstly confirm that folate receptor α (FRα) is a new generation of lysosome-targeting receptor (LTR) of LYTAC, facilitating the transport of membrane proteins to lysosomes to realize degradation. Moreover, novel FRTACs are constructed by a new “polyvalent crosslinking strategy”, instead of the traditional “one folate conjugating one drug strategy”. Polyvalency creates avidity, allowing FRTACs crosslinking FRα to dramatically improve the degradation efficiency. As a result, the optimized FRTACs, including EGFR-targeting FR-Ctx, PD-L1-targeting FR-Atz, TROP2-targeting FR-Stz, and HER2-targeting FR-Ttz, successfully eliminate cell surface targets with a subnanomole activity. Mechanism investigation reveals that FRTACs trigger targets degradation in a FRα- and lysosomal-dependent manner. Besides, FR-Ctx reduces cancer cell proliferation, and FR-Atz increases the cytotoxicity of T cells toward tumor cells. Furthermore, FR-Atz exhibits potent degradation efficiency of PD-L1 in vivo and elicits tumor-specific immune responses by switching the tumor immune microenvironment from a suppressed state to an activated state in both RM-1 mice model and humanized PD-1/PD-L1 B16F10 mice model. To our knowledge, FRTACs are the most potent protein degrader ever reported. The novel FRTACs will expand the application of FRα and provide a new platform for designing tumor-targeting LYTACs.
HostingRepository	PRIDE
AnnounceDate	2025-05-30
AnnouncementXML	Submission_2025-05-30_02:09:37.026.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dian Xiao
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2024-12-03 03:05:48	ID requested
⏵ 1	2025-05-30 02:09:37	announced

10.1038/S41589-025-01924-1;

submitter keyword: lysosome-targeting chimeras, polyvalent strategy,targeted protein degradation, folate receptor

Dian Xiao
contact affiliation	National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
contact email	be_xiaodian@163.com
lab head
Dian Xiao
contact affiliation	National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology
contact email	be_xiaodian@163.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/05/PXD058523

PRIDE project URI

• PRIDE
  1. PXD058523
     1. Label: PRIDE project
     2. Name: Development of polyvalent folate receptor-targeting chimeras (FRTACs) for lysosomal degradation of membrane proteins