Oroxylin a promoted apoptotic extracellular vesicles transfer of glycolytic kinases to remodel immune microenvironment in hepatocellular carcinoma model

Abstract

Although oroxylin A, a natural flavonoid compound, suppressed progression of hepatocellular carcinoma, whether the tumor microenvironment especially the communication between cancer cells and immune cells was under its modulation remained obscure. Here we investigated the effect of extracellular vesicles from cancer cells elicited by oroxylin A on macrophages in vitro. The data shows oroxylin A elicits apoptosis-related extracellular vesicles through caspase-3-mediated activation of ROCK1in HCC cells, which regulates M1-like polarization of macrophage. Moreover, oroxylin A downregulates the population of M2-like macrophage and promotes T cells infiltration in tumor microenvironment, accompanied by suppression of HCC development and enhancement of immune checkpoint inhibitor treatment in mice model. Mechanistically, glycolytic proteins enriched in oroxylin A-elicited extracellular vesicles from HCC cells are transferred to macrophages where ROS-dependent NLRP3 inflammasome is activated, therefore contributing to anti-tumor phenotype of macrophage. Taken together, this study highlights that oroxylin A promotes metabolic shifts between tumor cells and immune cells, facilitates to inhibit tumor development, and improves immunotherapy response in HCC model.