Oroxylin A promotes cancer cell-to-macrophage communication and improves
immunotherapy in hepatocellular carcinoma model
- Peiwen Wang,
- Xuefeng Zhang,
- Zhi Feng,
- Yufang Tang,
- Xiaolei Han,
- Tianxiao Mao,
- Sichan Li,
- Zhiyu Li,
- Qinglong Guo,
- Xiaobo Zhang
Abstract
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.