Comprehensive multi-omics analysis identifies transferrin receptor as a therapeutic target in esophageal cancer

This study aimed to identify novel biomarkers for esophageal cancer (ESCA) through multi-omics approaches and to explore their roles in disease progression. We analyzed the cellular heterogeneity of ESCA samples using single-cell RNA sequencing data, and transcriptomic analysis revealed differentially expressed genes between ESCA and normal tissues. By integrating gene expression quantitative trait loci analysis with genome-wide association studies, we identified the key gene transferrin receptor (TFRC) as being associated with ESCA. Both pan-cancer and ESCA-specific analyses indicated that increased TFRC expression is linked to poor prognosis and drug metabolism. Additionally, high TFRC expression was associated with reduced immune cell infiltration and downregulation of immune checkpoint genes. Multiplexed immunofluorescence assays further revealed that elevated TFRC expression is associated with immune evasion, negatively correlating with CD8⁺ T cell infiltration and positively correlating with M2 macrophage infiltration. Furthermore, our findings support a model in which TFRC modulates iron availability to influence the survival and activity of tumor cells, rather than primarily driving lipid peroxidation or ferroptosis. TFRC knockdown enhanced M1 macrophage polarization and CD8⁺ T cell infiltration. The differential expression of TFRC in the tumor epithelium and stroma highlights its significant role in immune evasion. In conclusion, TFRC plays a critical role in the development of ESCA and its immune escape mechanisms, suggesting that it may serve as a potential target for cancer immunotherapy.