Enhancing immunotherapy efficacy in oral cancer through AKB-9778-mediated vascular normalization

Tumor vasculature exhibit numerous abnormal features distinct from those of healthy vessels, potentially advancing tumor development by establishing an aberrant microenvironment. Therefore, vascular normalization has proven to be an effective tactic for substantially enhancing treatment efficacy across multiple tumors. However, the methods to attain vascular normalization may vary among tumor types. VE-PTP, expressed exclusively in vascular endothelial cells (ECs) and acting as a critical suppressor of vascular maturity and functionality, is upregulated in oral cancer due to hypoxia. In this study, we explored the effect and mechanism of AKB-9778, a competitive inhibitor of VE-PTP, in promoting vascular normalization of oral cancer. Initially, we showed that AKB-9778 can slow down tumor progression by fostering vascular normalization in a murine OSCC model. This was evidenced by improvements in vessel density, pericyte coverage, local hypoxia, and vascular permeability. RNA sequencing additionally indicated that the ECs of tumor vasculature exhibit abnormal alterations in adhesion molecules, and AKB-9778 treatment might facilitate vascular normalization by modulating lipid metabolism pathways, especially HSD17B7-regulated steroid biosynthesis. AKB-9778 treatment significantly up-regulated the HSD17B7 expression, thereby restoring the lipid content in tumor ECs. Moreover, this restoration of lipid metabolism mediated by HSD17B7 was associated with improved adhesion molecule expression and vascular normalization, facilitating immune cell infiltration and contributing to AKB-9778's anti-tumor effects. Finally, we verified the effects and safety of combined AKB-9778 treatment on improving the efficacy of anti-PD-1 immunotherapy. In summary, this study revealed the mechanism and potential application of AKB-9778-induced vascular normalization in patients with oral cancer.