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TitleMunc13-4 mediates tumor immune evasion by regulating the sorting and secretion of PD-L1 via exosomes.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 9080, Year 2025
Publish dateOct 13, 2025
AuthorsChuqi Liu / Dexiang Liu / Xiang Zheng / Jiali Guan / Xinyan Zhou / Haikun Zhang / Shen Wang / Qiubai Li / Gan Lu / Jun He / Cong Ma /
PubMed AbstractTumor-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 ...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.
External linksNat Commun / PubMed:41083534 / PubMed Central
MethodsEM (single particle)
Resolution3.42 - 4.38 Å
Structure data

62922

9la9

EMDB-62922, PDB-9la9:
Munc13-4-Rab27a complex with GppNHp
Method: EM (single particle) / Resolution: 4.38 Å

EMDB-63239: Munc13-4-Rab27a complex consensus map
Method: EM (single particle) / Resolution: 3.42 Å

Chemicals

ChemComp-GNP:
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GppNHp, GMPPNP, energy-carrying molecule analogue*YM

Source
  • homo sapiens (human)
KeywordsEXOCYTOSIS / Vesicle tethering / Familial hemophagocytic lymphohistiocytosis type 3 /FHL3 / Griscelli syndrome type 2 /GS2

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