PXD075012

PXD075012 is an original dataset announced via ProteomeXchange.

Title	Ceramide Disrupts TM9SF2-PGK1 Axis to Redirect PD-L1 Trafficking and Enhance Antitumor Immunity
Description	The programmed cell death protein 1 (PD-1) / programmed death-ligand 1 (PD-L1) axis represents a cornerstone of cancer immunotherapy, yet the dynamic shuttling of PD-L1 between endosomal recycling and lysosomal degradation routes limits durable responses. Using a CRISPR screen targeting glycosphingolipid metabolism, we identify transmembrane 9 superfamily member 2 (TM9SF2) as a key regulator of PD-L1 levels. TM9SF2 orchestrates a dual mechanism: it recruits phosphoglycerate kinase 1 (PGK1) to promote PD-L1 recycling to the plasma membrane while dismantling the huntingtin-interacting protein 1-related protein (HIP1R)-mediated lysosomal degradation pathway. Genetic or pharmacological disruption of the TM9SF2-PGK1 complex depletes PD-L1 levels and boosts antitumor immunity. Further, the endogenous ceramide species Cer(d18:1/26:0) destabilizes this complex, triggering PD-L1 lysosomal destruction and potentiating antitumor immunity. These findings delineate a ceramide-gated sorting mechanism within the endosomal network, revealing a druggable metabolic switch to disrupt immune evasion and amplify checkpoint blockade efficacy.
HostingRepository	iProX
AnnounceDate	2026-02-27
AnnouncementXML	Submission_2026-05-20_01:14:15.111.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mengmeng Wang
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2026-02-27 18:59:11	ID requested
1	2026-02-27 18:59:26	announced
⏵ 2	2026-05-20 01:14:16	announced	2026-05-20: Add info.

Zheng Y, Yang F, Wang M, Wang Z, Zhang X, Huo C, Zhang Y, Nie A, Lyu W, Dong A, Li M, Du Z, Zhou S, Song L, Jiang W, Gu B, Zhao W, Dong T, Ceramide disrupts TM9SF2-PGK1 axis to redirect PD-L1 trafficking and enhance antitumor immunity. Nat Commun, 17(1):(2026) [pubmed]

submitter keyword: PD-L1, endosome, TM9SF2, anti-tumor, ceramide, immunotherapy

Ting Dong
contact affiliation	Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College
contact email	tingdong2025@pumc.edu.cn
lab head
Mengmeng Wang
contact affiliation	Shandong University
contact email	wmm20201101@163.com
dataset submitter

iProX dataset URI