PXD064363

PXD064363 is an original dataset announced via ProteomeXchange.

Title	Targeting LRBA triggers CTLA4 degradation and antitumor immunity for cancer immunotherapy
Description	The lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency causes severe autoimmune diseases and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) loss in humans. However, the impact of LRBA on antitumor immunity remains understudied. Here, we identified the role of LRBA in antitumor immunity and developed a novel immunotherapy for cancers. Interestingly, LRBA was negatively associated with antitumor immunity in human patients. Using high-throughput screening and subsequent structure-based hit optimization, we discovered a small molecule LC427 that bound directly to LRBA, and selectively interfered with the LRBA-CTLA4 interaction. This mechanistically unique LC427 facilitated the lysosomal degradation of CTLA4, and bolstered survival and functions of activated T cells. Importantly, orally administrated LC427 increased tumor-infiltrating CD8+ T cells and displayed effective antitumor activity in tumor-bearing mouse models. Notably, LC427 did not induce typical irAEs observed with immune checkpoint inhibitors in colitis models. Our study demonstrates that targeting LRBA offers a novel and effective strategy with a favorable safety profile, highlighting the potential of LRBA-based immunomodulatory therapies in the treatment of cancers.
HostingRepository	PRIDE
AnnounceDate	2026-01-23
AnnouncementXML	Submission_2026-01-23_01:18:38.240.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Xiaolu Ge
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2025-05-28 02:41:02	ID requested
⏵ 1	2026-01-23 01:18:39	announced

10.1038/s41467-025-67365-5;

Ge X, Yu L, Zhang L, Jia L, Meng M, He J, Bu F, Song Y, Sun G, Lv S, Mei D, Yang Y, Xu D, Zhang J, Zhang S, Wang C, Jia D, Chen Y, Gao Y, He B, Targeting LRBA triggers CTLA4 degradation and antitumor immunity for cancer immunotherapy. Nat Commun, 17(1):623(2025) [pubmed]

submitter keyword: None

Baokun He
contact affiliation	Laboratory of Molecular Pharmacology and Drug Discovery, Institute of Chinese Materia Medica, The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, China
contact email	hbk3397@gzucm.edu.cn
lab head
Xiaolu Ge
contact affiliation	Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University
contact email	1052026862@qq.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/2026/01/PXD064363

PRIDE project URI

• PRIDE
  1. PXD064363
     1. Label: PRIDE project
     2. Name: Targeting LRBA triggers CTLA4 degradation and antitumor immunity for cancer immunotherapy