Acquisition of Vimentin by trogocytosis inhibits the NK cell-mediated immune response against CTCs

Natural killer (NK) cells frequently exhibit an exhausted state, which facilitates immune escape of circulating tumour cells (CTCs). However, the underlying mechanisms of NK cell dysfunction remain elusive. In this study, we identify 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 non-endogenous proteins in NK cells isolated from CTC detectable oral cancer patients, but not in those from CTC non-detectable patients. High-throughput proteomic analysis, flow cytometry and confocal microscopy results 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 the 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. Clinically, the frequency of Vimentin (+) NK cells correlates with CTC burden and tumor recurrence in oral cancer patients. Our study reveals trogocytosis as a conduit for the tumor-induced exhaustion of NK cells and proposes targeting Vimentin transfer as a therapeutic strategy to counteract tumor recurrence.