Extracellular vesicle-associated LMP1 from EBV-positive nasopharyngeal carcinoma induces LIF-mediated immunosuppressive macrophage polarization and impairs anti-tumor immunity.

Authors

Tzu-Tung Liu, Kai-Ping Chang, Meng-Hsin Li, Yun-Hua Sui, Fang-Yu Tsai, Hsuan-Chung Chen, Chen-Han Huang, Ya-Wen Chen, Shih Sheng Jiang, Shu-Chen Liu

Published in

Cancer letters. Pages 218892. Oct 14, 2026. Epub Oct 14, 2026.

Abstract

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is characterized by a highly infiltrated yet immunosuppressive tumor microenvironment (TME), in which tumor-associated macrophages (TAMs) contribute to disease progression. Here, we identify an extracellular vesicle (EV)-mediated LMP1-NF-κB-LIF signaling axis that promotes macrophage reprogramming and immune suppression in NPC. Single-cell transcriptomic analysis revealed that EV exposure induces transcriptional remodeling across tumor and immune-cell populations, accompanied by an increased proportion of TAMs within the myeloid compartment. NPC-derived EVs were taken up by macrophages, where EV-associated LMP1 induced NF-κB activation, LIF expression, and polarization toward an immunosuppressive phenotype. Loss- and gain-of-function studies, together with structure-function analyses of the LMP1 CTAR1/CTAR2 domains, further supported the requirement of these CTAR domains for efficient NF-κB activation and LIF induction. Functionally, EV-educated macrophages exhibited impaired phagocytic activity and promoted inhibitory T-cell responses. In zebrafish, 3D spheroid, and mouse xenograft models, EV-educated macrophages promoted NPC growth and vascular dissemination, whereas blockade of LIF signaling with soluble LIFR attenuated these effects. Tumor LIF expression positively correlated with CTLA4 expression. In NPC tissues, LIF expression was preferentially associated with stromal macrophages, and elevated stromal LIF expression was associated with metastasis, advanced nodal disease, and advanced clinical stage. Stromal immune-cell LMP1 expression also correlated with LIF expression and was higher in patients who developed metastasis. Collectively, these findings support an EV-associated LMP1-NF-κB-LIF axis that links EBV-positive NPC cells to macrophage-mediated immune suppression and tumor progression and provide a basis for further investigating this pathway as a potential therapeutic target.

PMID:
42874988
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.

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