OXPHOS inhibitor IACS010759 suppresses tumor growth by modulating autophagy in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is a prevalent and highly malignant digestive tract cancer with poor prognosis. Cancer cells generally exhibit increased glycolytic activity, and it was previously believed that oxidative phosphorylation (OXPHOS) is downregulated in all cancers. However, recent studies have shown increased OXPHOS activity in some tumors, even alongside active glycolysis. This has led to the exploration of targeting elevated OXPHOS as a therapeutic strategy. Despite this, the role of OXPHOS in ESCC tumorigenesis and progression remains unclear. In this study, we found that OXPHOS-related genes are highly expressed in ESCC cell lines and tissues, and this elevated expression correlates with clinical prognosis. The OXPHOS inhibitor IACS-010759 suppressed ESCC cell proliferation, clonogenicity, and migration, while disrupting mitochondrial morphology and function. Furthermore, IACS-010759 inhibited xenograft tumor growth in nude mice. Treatment with IACS-010759 also inhibited autophagy and activated the AKT/mTOR pathway in ESCC cells. The autophagy inducer rapamycin counteracted the inhibitory effects of IACS-010759, indicating that IACS-010759 inhibits ESCC autophagy via AKT/mTOR activation, thereby exerting anti-tumor effects. Interestingly, inhibiting OXPHOS increased glycolytic activity. Combining IACS-010759 with the glycolysis inhibitor 2-DG resulted in a significant synergistic anti-tumor effect in ESCC cells and xenografts. In conclusion, our findings suggest that the OXPHOS pathway may serve as a promising therapeutic target for ESCC.