TLR4 promotes ESCC progression by driving inflammation and metabolic reprogramming through SLC39A10-mediated zinc homeostasis.

BACKGROUND: Toll-like receptor 4 (TLR4), a key pattern recognition receptor in innate immunity, is frequently overexpressed in various malignancies including esophageal squamous cell carcinoma (ESCC). While TLR4’s oncogenic potential has been established, its functional contribution to ESCC pathogenesis remains incompletely understood, and the therapeutic potential of TLR4 signaling inhibition warrants further investigation. METHODS: Comprehensive expression profiling of TLR4 and SLC39A10 was performed in: (1) clinical ESCC specimens, (2) established ESCC cell lines, and (3) 4-nitroquinoline 1-oxide (4-NQO)-induced spontaneous and xenograft tumor models. Functional characterization included TLR4 genetic ablation, zinc chelation experiments, and systematic analysis of glycolytic metabolism. Glycolytic flux was quantified through extracellular acidification rate (ECAR), oxygen consumption rate (OCR), glucose uptake efficiency, and lactate secretion assays. Zinc homeostasis regulation was examined using pharmacological modulators combined with SLC39A10 genetic silencing approaches. RESULTS: TLR4 activation upregulated SLC39A10 expression, resulting in intracellular zinc accumulation that simultaneously potentiated NF-κB-dependent inflammatory signaling and HIF1α-mediated glycolytic activation. Genetic TLR4 ablation significantly attenuated tumorigenesis in vivo, while SLC39A10 knockdown abrogated TLR4’s oncogenic effects. CONCLUSIONS: Our study identifies a previously unrecognized TLR4/SLC39A10/zinc pathway that drives ESCC progression through dual modulation of inflammatory and metabolic pathways. These findings provide the first experimental evidence connecting zinc homeostasis to TLR4-mediated metabolic reprogramming in cancer, revealing novel therapeutic targets for ESCC treatment. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07560-6.