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<p>Natural killer (NK) cells frequently exhibit an exhausted state, which facilitates immune escape of circulating tumor cells (CTCs). However, the underlying mechanisms of NK cell dysfunction remain elusive. In this study, we identified a novel immune evasion mechanism whereby tumor cells deliver Vimentin to NK cells via NKp46-dependent trogocytosis, thereby impairing NK cell cytotoxicity. We observed the expression of nonendogenous proteins in NK cells isolated from CTCs from oral cancer patients but not in those from nondetectable patients. High-throughput proteomic analysis, flow cytometry, and confocal microscopy revealed that vimentin, a protein that is not endogenously expressed in NK cells, was significantly enriched in NK cells via NKp46-dependent trogocytosis. The tail domain of trogocytosed vimentin competed with CDC42 for binding to ARHGEF7 and inhibited its exchange activity. This disruption impaired CDC42-mediated actin polymerization, thus suppressing NK cell cytotoxicity. By delivering vimentin to NK cells, CTCs can suppress and evade attacks from NK cells. Crucially, pharmacological inhibition of vimentin trogocytosis increased the efficacy of NK cells in clearing CTCs in vivo and that of NK cell-based adoptive immunotherapies. Clinically, the frequency of vimentin (+) NK cells is correlated with the CTC burden and tumor recurrence in cancer patients. Our study reveals that trogocytosis acts as a conduit for the tumor-induced exhaustion of NK cells and proposes targeting Vimentin transfer as a therapeutic strategy to counteract tumor recurrence.</p>

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Acquisition of Vimentin by trogocytosis inhibits the NK cell-mediated immune response against circulating tumour cells (CTCs)

  • 期刊论文

  • 发表日期：

    2026年6月22日

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  • Lu Zhao,
  • Ran Li,
  • Xiao-Yan Meng,
  • Yu-Xiang Guo,
  • Liu Liu,
  • Si-Yi Li,
  • Zhonglong Liu,
  • Long-Wei Hu,
  • Hai-Long Ma,
  • Chao-Ji Shi,
  • Qin Xu,
  • Yue He

摘要

Natural killer (NK) cells frequently exhibit an exhausted state, which facilitates immune escape of circulating tumor cells (CTCs). However, the underlying mechanisms of NK cell dysfunction remain elusive. In this study, we identified a novel immune evasion mechanism whereby tumor cells deliver Vimentin to NK cells via NKp46-dependent trogocytosis, thereby impairing NK cell cytotoxicity. We observed the expression of nonendogenous proteins in NK cells isolated from CTCs from oral cancer patients but not in those from nondetectable patients. High-throughput proteomic analysis, flow cytometry, and confocal microscopy revealed that vimentin, a protein that is not endogenously expressed in NK cells, was significantly enriched in NK cells via NKp46-dependent trogocytosis. The tail domain of trogocytosed vimentin competed with CDC42 for binding to ARHGEF7 and inhibited its exchange activity. This disruption impaired CDC42-mediated actin polymerization, thus suppressing NK cell cytotoxicity. By delivering vimentin to NK cells, CTCs can suppress and evade attacks from NK cells. Crucially, pharmacological inhibition of vimentin trogocytosis increased the efficacy of NK cells in clearing CTCs in vivo and that of NK cell-based adoptive immunotherapies. Clinically, the frequency of vimentin (+) NK cells is correlated with the CTC burden and tumor recurrence in cancer patients. Our study reveals that trogocytosis acts as a conduit for the tumor-induced exhaustion of NK cells and proposes targeting Vimentin transfer as a therapeutic strategy to counteract tumor recurrence.