Background Esophageal squamous cell carcinoma (ESCC) is an environment-related cancer by its spatial distribution characteristics. An increasing number of studies have demonstrated crucial correlations between ESCC and multiple environmental heavy metal exposures, while the roles of the synergistic effect of heavy metals in ESCC remains unclear.

Methods Based on a case-control study of 131 pairs of ESCC patients and healthy control, several serum and urine metals were detected by ICP-MS. LASSO and Bayesian kernel machine regression (BKMR) were used to explore the combined effect of metals on the incidence of ESCC. An in vitro model for co-exposure of elevated cadmium and zinc deficiency (Cd⁺/Zn^-) was established to clarify molecular mechanisms in esophageal cancer malignant progression.

Results Multiple metals were changed in serum and urine ESCC patients, among which abnormal internal co-exposure of Cd⁺/Zn^- was identified by LASSO and BKMR. Cd⁺/Zn^- drove migration, invasion, and vasculogenic mimicry of ESCC cells. We found mtDNA was released into the cytoplasm through the mitochondrial permeability transition pore and further enhanced stemness. The mechanism underlying these changes may involve Cd⁺/Zn^- inhibited MTF1-TFAM axis, which confers disorganized activation of cGAS-STING pathways and Sox2-manipulated cancer stemness.

Conclusions Our study identified a novel pattern of metal co-exposure in ESCC malignant progression, which may contribute to further demonstrating the potential roles of trace metals-based early identification and therapies.