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. 2025 Aug 15:375:123713.
doi: 10.1016/j.lfs.2025.123713. Epub 2025 May 19.

Tumor cell-derived microparticles containing MTX (MTX-TMPs) in the treatment of cholangiocarcinoma by modulating MDSCs

Qi Zhang  1 , Saifei Wang  2 , Bin Liu  1 , Xiaolin Jiang  1 , Xiaojun Sui  1 , Zehan Liu  1 , Dihua Li  1 , Xiangyang Yu  1 , Ximo Wang  1 , Hui Zhang  3 , Jing Xun  4 , Dapeng Zhang  5
Affiliations

Tumor cell-derived microparticles containing MTX (MTX-TMPs) in the treatment of cholangiocarcinoma by modulating MDSCs

Qi Zhang et al. Life Sci. .

Abstract

Background: Cholangiocarcinoma (CCA) is the second most common malignant tumor of the liver and lacks efficient treatments. Our previous study showed that tumor cell-derived microparticles (TMPs) containing MTX (MTX-TMPs) effectively drain the obstruction of the bile duct; however, the underlying mechanism remains unclear.

Methods: Liver function indices and immune cell percentages were analyzed in CCA patients after treatment with MTX-TMPs. An intrahepatic cholangiocarcinoma (ICC) mouse model was established to assess the effect of MTX-TMPs on ICC progression and immunomodulation. The effects of MTX-TMPs on the proinflammatory effects of CCA cells, and on the myeloid-derived suppressor cells (MDSCs) recruitment, migration, apoptosis, differentiation and immunosuppressive functions were investigated using human and mouse MDSCs.

Results: MTX-TMPs exhibited significant efficacy in treating patients with CCA, including increasing the proportion of CD45+cells, CD4+T, CD8+T, NK, and NKT cells in patients' bile or peripheral blood, and decreasing the proportion of MDSCs, without inducing abnormalities in liver function parameters. Animal experiments indicated that MTX-TMPs significantly alleviated the progression of ICC and reduced the proportion of MDSCs. The results of cell-based experiments indicated that MTX-TMPs inhibited the expression and secretion of inflammatory and chemotactic factors and the activation of STAT3 and NF-κB in CCA cells. Additionally, MTX-TMPs promoted MDSCs apoptosis, inhibited the recruitment of MDSCs to CCA cells, and suppressed the differentiation and immunosuppressive functions of MDSCs by inhibiting the STAT/CEBPβ signaling pathway.

Conclusion: Our results indicated that MTX-TMPs alleviated CCA progression by regulating MDSCs, which provide an effective strategy for the treatment of CCA.

Keywords: Cholangiocarcinoma; Extracellular vesicles; MTX-TMPs; Myeloid-derived suppressor cells; Tumor immune microenvironment; Tumor immunology.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no relevant financial or non-financial interests that could have influenced the outcome of this study. Specifically, no funding was received for this research, and the authors have no conflicts of interest, including personal, academic, or commercial relationships, that could bias the results or interpretations presented in this manuscript.