TNBC患者血浆中的小型细胞外囊泡(sEV)促进了T细胞功能障碍和肿瘤发展。我们展示了肿瘤细胞来源的外泌体(TEX)携带表面PDL-1、PD-1、Fas、FasL、TRAIL、CTLA-4和TGF-β1，诱导CD8+T和CD4+T细胞凋亡，但不伤害B细胞和NK细胞。阻断TEX诱导受体/配体信号的抑制剂以及经蛋白酶K或热处理的TEX对预防T细胞凋亡无效。赛托卡拉霉素D、地诺索尔或Pit Stop 2部分抑制TEX的摄取，但不能防止T细胞凋亡。TEX进入T细胞诱导线粒体释放细胞色素C和Smac，并导致细胞质中caspase-3和PARP的裂解。在正在凋亡过程中的T细胞中，存活蛋白的表达减少。独立于外部死亡受体信号，TEX进入T细胞诱导线粒体应激，引发无情的内源性凋亡，这是肿瘤携带者激活的T细胞死亡的原因。癌症血浆中TEX的丰度代表了对移植T细胞的危险，限制了其治疗潜力。© 2023. Springer Nature Limited.

Small extracellular vesicles (sEV) in TNBC patients' plasma promote T cell dysfunction and tumor progression. Here we show that tumor cell-derived exosomes (TEX) carrying surface PDL-1, PD-1, Fas, FasL, TRAIL, CTLA-4 and TGF-β1 induce apoptosis of CD8+T and CD4+T cells but spare B and NK cells. Inhibitors blocking TEX-induce receptor/ligand signals and TEX pretreatments with proteinase K or heat fail to prevent T cell apoptosis. Cytochalasin D, Dynosore or Pit Stop 2, partly inhibit TEX uptake but do not prevent T cell apoptosis. TEX entry into T cells induces cytochrome C and Smac release from mitochondria and caspase-3 and PARP cleavage in the cytosol. Expression of survival proteins is reduced in T cells undergoing apoptosis. Independently of external death receptor signaling, TEX entry into T cells induces mitochondrial stress, initiating relentless intrinsic apoptosis, which is responsible for death of activated T cells in the tumor-bearing hosts. The abundance of TEX in cancer plasma represents a danger for adoptively transferred T cells, limiting their therapeutic potential.© 2023. Springer Nature Limited.