Fraxinellone Inhibited Immune Evasion and Cell Growth by Inactivating HIF‐1α/STAT3/PD‐L1 Signaling in Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma (ESCC), the predominant histological subtype constituting approximately 80% of all esophageal malignancies worldwide, represents a significant global disease burden with distinct geographical predilection. Fraxinellone (FRA) was reported to function as a tumor suppressor in several tumors, while the role of FRA in ESCC remains unclear. In the present study, we found that FRA treatment significantly inhibited cell proliferation and colony formation of ESCC cells. On the contrary, FRA treatment promoted cell apoptosis of ESCC cells by downregulating Bcl-2 protein and upregulating Bax and C-caspase3 proteins. Besides, FRA pretreatment suppressed proliferation and viability of CD8⁺ T cells but facilitated cell apoptosis in co-culturing system. Moreover, FRA pretreatment restrained immune evasion by attenuating CD8⁺ T cell activation. Mechanistically, FRA effectively inactivated HIF-1α/STAT3/PD-L1 signaling in ESCC cells and xenograft tumors. Ultimately, FRA treatment inhibited tumor growth in vivo. In conclusions, FRA inhibited ESCC cell growth and immune evasion by inactivating HIF-1α/STAT3/PD-L1 signaling in vitro and vivo. This study suggested that FRA may serve as a potential therapeutic agent for ESCC treatment.