Anti-angiogenesis and anti-immunosuppression gene therapy through targeting COUP-TFIIin an in situ glioblastoma mouse model

Glioblastoma (GBM) is the most common and aggressive primary brain cancer; angiogenesis and immunosuppression exacerbate GBM progression. COUP-TFIIdemonstrates pro-angiogenesis activity; however, its role in glioma progression remains unclear. This study revealed that COUP-TFIIpromotes angiogenesis in gliomas by inducing transdifferentiation of glioma cells into endothelial-like cells. Mechanistic investigation suggested that COUP-TFIIas a transcription factor exerts its function via binding to the promoter of TXNIP. Interestingly, COUP-TFIIknockdown attenuated tumorigenesis and tumor progression in an immunocompetent mouse model but promoted tumor progression in an immuno-deficient mouse model. As an explanation, repression of COUP-TFIIinduces cellular senescence and activates immune surveillance in glioma cells in vitro and in vivo. In addition, we used heparin–polyethyleneimine (HPEI) nanoparticles to deliver COUP-TFIIshRNA, which regulated tumor angiogenesis and immunosuppression in an in situ GBM mouse model. This study provides a novel strategy and potential therapeutic targets to treat GBM.