Several reports have demonstrated that Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1), which is transferred by extracellular vesicles (EVs) or exosomes, can promote cancer progression. However, its mechanism is still not fully understood. In the present study, we demonstrated that EV packaged LMP1 can activate normal fibroblasts (NFs) into cancer-associated fibroblasts (CAFs). The NF-κB p65 pathway is the key signal that promotes the activation of NFs to CAFs in nasopharyngeal carcinoma (NPC). In activated CAFs, aerobic glycolysis and autophagy were increased. Moreover, glucose uptake and lactate production were decreased, and mitochondrial activity in tumor cells was enhanced, which supported the Reverse Warburg Effect (RWE). During this process, upregulation of MCT4 in CAFs and MCT1 in tumor cells was observed. The NF-κB p65 pathway also plays an important role in the regulation of MCT4. Furthermore, co-culture with CAFs promoted the proliferation, migration and radiation resistance of NPC cells. And EV packaged LMP1 promoted tumor proliferation and pre-metastatic niche formation by activating CAFs in vivo. Our findings indicate that EV packaged LMP1-activated CAFs promote tumor progression via autophagy and stroma-tumor metabolism coupling.

几篇报道表明，由细胞外囊泡（EVs）或外泌体转移的爱泼斯坦-巴尔病毒（EBV）潜伏膜蛋白1（LMP1）可以促进癌症进展。但是，其机制仍未完全理解。在本研究中，我们证明了EV包装的LMP1可以将正常的成纤维细胞（NFs）激活为癌症相关的成纤维细胞（CAFs）。NF-κBp65通路是在鼻咽癌（NPC）中促进NFs活化为CAFs的关键信号。在激活的CAF中，有氧糖酵解和自噬增加。此外，减少了葡萄糖的摄取和乳酸的产生，并且增强了肿瘤细胞中的线粒体活性，这支持了逆华伯格效应（RWE）。在此过程中，观察到CAF中MCT4的上调和肿瘤细胞中MCT1的上调。NF-κBp65途径在MCT4的调控中也起着重要作用。此外，与CAF的共培养促进了NPC细胞的增殖，迁移和辐射抗性。EV包装的LMP1通过体内激活CAF促进肿瘤增殖和转移前的生态位形成。我们的发现表明，EV包装的LMP1激活的CAF通过自噬和基质-肿瘤代谢耦合促进肿瘤进展。