Munc13-4 mediates tumor immune evasion by regulating the sorting and secretion of PD-L1 via exosomes

Chuqi Liu, Dexiang Liu, Xiang Zheng, Jiali Guan, Xinyan Zhou, Haikun Zhang, Shen Wang, Qiubai Li, Gan Lu, Jun He () and Cong Ma ()
Additional contact information
Chuqi Liu: Huazhong University of Science and Technology
Dexiang Liu: Huazhong University of Science and Technology
Xiang Zheng: Huazhong University of Science and Technology
Jiali Guan: Chinese Academy of Sciences
Xinyan Zhou: Huazhong University of Science and Technology
Haikun Zhang: Huazhong University of Science and Technology
Shen Wang: Huazhong University of Science and Technology
Qiubai Li: Huazhong University of Science and Technology
Gan Lu: Huazhong University of Science and Technology
Jun He: Chinese Academy of Sciences
Cong Ma: Huazhong University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-24

Abstract: Abstract Tumor-derived exosomes carry programmed death-ligand 1 (PD-L1), which binds programmed cell death protein 1 (PD-1) on T cells, suppressing immune responses locally and systemically. However, the mechanisms governing exosomal PD-L1 sorting and secretion remain elusive. Here, we identify Munc13-4 as a crucial regulator of this process. Deletion of Munc13-4 in breast tumors enhances T cell-mediated anti-tumor immunity, suppresses tumor growth, and improves the efficacy of immune checkpoint inhibitors. Mechanistically, Munc13-4 collaborates with hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), Rab27, and SNAREs to facilitate PD-L1 sorting and secretion via exosomes. Cryogenic electron microscopy (cryo-EM) analysis of the Munc13-4–Rab27a complex provide structural insights into exosome secretion. Importantly, PD-L1 sorting relies on a ternary complex composed of Munc13-4, PD-L1 and HRS, which is regulated by interferon gamma (IFNγ) signaling. A designed peptide that disrupts Munc13-4–PD-L1 interaction impedes PD-L1 sorting, enhances antitumor immunity, and suppresses tumor growth, highlighting the therapeutic potential of targeting this pathway.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-64149-9 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_s41467-025-64149-9

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

DOI: 10.1038/s41467-025-64149-9

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 ().