Astragaloside IV-PESV Repressed T Cell Immunosuppression by Inhibiting PD-L1 Expression in Prostate Cancer through STAT3 Pathway

Background. Prostate cancer (PCa) is a major threat to men's health worldwide, and there is an urgent need to find a supportive strategy to improve traditional PD-1/PD-L1 targeted immunotherapy. Our previous research identified astragaloside IV and polypeptide extract from scorpion venom (PESV) as the main active components of the astragalus-scorpion drug pair for treating PCa. In this study, we wanted to continue exploring the modulatory effect of astragaloside IV-PESV on the immune microenvironment of tumors further to investigate the antitumor efficacy mechanism of astragaloside IV-PESV. Methods. First, molecular docking was performed to verify whether astragaloside IV and PESV could bind to STAT3 and PD-L1. Next, we performed mouse tumorigenesis experiments to explore the role of astragaloside IV-PESV. Additionally, we further validated the effects of astragaloside IV-PESV on the STAT3/PD-L1 pathway and immunity by in vitro cellular experiments. Furthermore, we overexpressed STAT3 and validated the effects of overexpression of STAT3 on cellular function, T cell activation, and immune escape in vitro and in vivo. Results. Molecular docking revealed astragaloside IV and PESV bound to STAT3 and PD-L1. Astragaloside IV-PESV led to notable tumor tissue volume and weight repression and inhibited tumor immunity and STAT3/PD-L1 pathway-related protein expressions. In vitro, astragaloside IV-PESV suppressed PD-L1 expression by inhibiting STAT3 signaling to modulate immunity. In contrast, overexpression of STAT3 restored PCa cell proliferation, migration, and invasion inhibition by astragaloside IV-PESV. In addition, overexpression of STAT3 restored the promoting effect of astragaloside IV-PESV on T cell activation. Finally, in vivo experiments further illuminated that overexpression of STAT3 restored the immune escape effect of astragaloside IV-PESV on the tumor. Conclusion. Astragaloside IV-PESV improved T cell immune escape by inhibiting PD-L1 expression in PCa through the STAT3 pathway.