Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC.

肿瘤来源的细胞外囊泡是肿瘤发生过程中细胞间通讯的重要介质。在这里，我们证明了肝细胞癌（HCC）衍生的外体重塑肿瘤微环境，以促进HCC以外体PKM2依赖的方式发展。源自HCC的外泌体PKM2不仅诱导单核细胞的代谢重编程，而且诱导细胞核中的STAT3磷酸化，从而上调分化相关的转录因子，从而导致单核细胞向巨噬细胞分化和肿瘤微环境重塑。在HCC细胞中，PKM2的磺酰化通过与ARRDC1的相互作用诱导其质膜靶向和随后的体外排泄。巨噬细胞分泌的细胞因子/趋化因子以CCL1-CCR8轴依赖性方式增强了HCC中的PKM2-ARRDC1关联，进一步促进了HCC细胞中PKM2的排泄，形成了用于肿瘤发生的前馈调节环。在临床上，在肝癌患者血浆中明确检测到外体PKM2。这项研究强调了外体PKM2重塑肿瘤微环境的机制，并揭示了外体PKM2作为HCC的潜在诊断标记。