STING inhibits the progression of esophageal squamous cell carcinoma by suppressing CPT1A-mediated fatty acid β-oxidation

Esophageal squamous cell carcinoma (ESCC) is characterized by high aggressiveness and poor prognosis. Metabolic reprogramming is a hallmark of ESCC, with lipid metabolism frequently upregulated. It has been shown that lipid metabolism, particularly fatty acid β-oxidation (FAO), plays an essential role in energy homeostasis, membrane biosynthesis, and tumor progression. Stimulator of interferon genes (STING), a key innate immune signaling molecule, also acts as a metabolic checkpoint by inhibiting Hexokinase 2, thereby limiting aerobic glycolysis and enhancing anti-tumor immune responses. In this study, we investigated the impact of STING on FAO and tumorigenesis in ESCC. We showed that the expression levels of STING were significantly reduced in ESCC compared to adjacent normal tissue. In the ESCC cell line KYSE-510, knockdown of STING significantly elevated lipid metabolites, decreased intracellular lipid droplets, and increased FAO products, whereas overexpression of STING inhibited ESCC cell proliferation and tumor progression by suppressing FAO. Targeted lipid metabolomic analyses revealed that STING interacted with carnitine palmitoyltransferase 1A (CPT1A), a key enzyme in FAO. STING promoted the ubiquitination and degradation of CPT1A by disrupting its interaction with USP15, a deubiquitinating enzyme. Treatment with the CPT1A inhibitor etomoxir (50 μM) reversed the increased FAO induced by STING depletion in KYSE-30 cells. In both in vitro and in vivo models, supplementation with palmitic acid rescued STING-induced growth inhibition, restoring tumor cell growth. In addition, STING knockout in 4-NQO-induced ESCC mice led to accelerated tumor progression, which could be mitigated by CPT1A inhibition. Our results suggest that reduced STING expression enhances FAO and promotes ESCC cell proliferation, implicating FAO suppression as a potential therapeutic strategy for ESCC.

CPT1A; STING; USP15; esophageal squamous cell carcinoma; etomoxir; fatty acid β-oxidation.