Ectosomal PKM2 Promotes HCC by Inducing Macrophage Differentiation and Remodeling the Tumor Microenvironment

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. [Display omitted] •HCC-cell-derived ectosomal PKM2 induces monocyte-to-macrophage differentiation•Remodeling tumor microenvironment by ectosomal PKM2 promotes HCC progression•Sumoylation facilitates PKM2 sorting into ectosomes in an ARRDC1-dependent manner•Macrophage-secreted CCL1 reinforces PKM2 ectosomal excretion in a feedforward loop Hou et al. demonstrate that sumoylation facilitates ectosomal excretion of PKM2 from HCC cells, which remodels the tumor microenvironment to promote HCC progression through inducing monocyte-to-macrophage differentiation. Macrophage-secreted CCL1 in tumor microenvironment further enhances ectosomal excretion of PKM2. The plasma ectosomal PKM2 is a potential early diagnostic marker for HCC.