PXD061780

PXD061780 is an original dataset announced via ProteomeXchange.

Title	Endosomal sorting regulates PD-L1 trafficking and enhances immunotherapy efficacy
Description	Immune-checkpoint inhibition affecting the PD-1/PD-L1 pathway is a robust clinical approach to treat cancer. Unfortunately, antibody-binding-caused PD-L1 internalization and recycling can lead to resistance and reduced clinical efficacy. Inhibiting lysosome-mediated PD-L1 degradation is necessary to preserve the PD-L1 level that recycles back to the cell membrane. It remains unclear whether there exists a specific mechanism that regulates the trafficking of PD-L1 into endosomes or lysosomes. We identified transmembrane-9 superfamily members 1-4 (TM9SF1-4) through a targeted CRISPR screen, with TM9SF2 emerging as a critical regulator. Mechanistically, TM9SF2 interacts with phosphoglycerate kinase 1 (PGK1), facilitating the endosomal recycling of PD-L1 back to the plasma membrane. Simultaneously, this interaction complex inhibits the pathway of lysosomal PD-L1 degradation via eliminating lysosome carrier HIP1R. Genetic or chemical inhibition of TM9SF2 or PGK1 reduced PD-L1 levels, enhancing the efficacy of immunotherapy. Furthermore, metabolomics-guided screening revealed that treatment with Cer(d18:1/26:0) or the overexpression of its synthase CERS3 disrupted the TM9SF2-PGK1 complex, shifting the process from endosomal recycling to lysosomal degradation. This transition led to a reduction in PD-L1 expression and increased immune responses in murine tumors. Our findings establish the TM9SF2-PGK1 complex as a signaling hub responsive to ceramide, regulating PD-L1 sorting in the endosomal system and contributing to cancer immune evasion. These insights highlight potential therapeutic strategies to augment immune responses by controlling PD-L1 trafficking.
HostingRepository	PRIDE
AnnounceDate	2026-06-08
AnnouncementXML	Submission_2026-06-07_16:18:58.917.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Fan Yang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2025-03-12 21:14:20	ID requested
⏵ 1	2026-06-07 16:18:59	announced

10.1038/s41467-026-70764-x;

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: Immune checkpoint inhibitor, PGK1,Endosomal sorting, TM9SF2, Ceramide, PD-L1, Immunotherapy

Wei Zhao
contact affiliation	Shandong University
contact email	15064112199@163.com
lab head
Fan Yang
contact affiliation	Shandong University
contact email	15064112199@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/2026/06/PXD061780

PRIDE project URI

• PRIDE
  1. PXD061780
     1. Label: PRIDE project
     2. Name: Endosomal sorting regulates PD-L1 trafficking and enhances immunotherapy efficacy