Oroxylin A promotes cancer cell-to-macrophage communication and improves immunotherapy in hepatocellular carcinoma model

Emerging evidence suggest that oroxylin A, a natural flavonoid compound, induces apoptosis in HCC through multiple mechanisms. However, whether oroxylin A-induced apoptosis could exhibit modulatory effect on tumor microenvironment remains unclear. Here we investigate the effect of oroxylin A on communication between cancer cells and macrophages in vitro and mouse model. The data shows oroxylin A elicits apoptosis-related extracellular vesicles through caspase 3-mediated ROCK1 activation in HCC cells, which are able to regulate M1-like polarization of macrophage. Moreover, oroxylin A downregulates the population of M2-like macrophage and increase in T cells infiltration in tumor microenvironment, accompanied with suppression of HCC development and enhancement of immune checkpoint inhibitor treatment. Mechanistically, glycolysis proteins enriched in oroxylin A-elicited extracellular vesicles from HCC cells is transferred to macrophages where it contributes to ROS-dependent NLRP3 inflammasome activation, therefore promoting anti-tumor phenotype of macrophage. Taken together, this study highlights oroxylin A promotes metabolic shifts between tumor cells and macrophages, facilitating to inhibit tumor development and improve immunotherapy response in HCC model.