Abstract
Cuproptosis involves a direct interaction with the tricarboxylic acid (TCA) lipid acylation components. This process intricately intersects with post-transcriptional lipid acylation (LA) and is linked to mitochondrial respiration and LA metabolism. Copper ions form direct bonds with acylated DLAT, promoting DLAT oligomerization, reducing Fe-S cluster proteins, and inducing a protein-triggered toxic stress response that culminates in cell demise. Simultaneously, the importance of immune contexture in cancer progression and treatment has significantly increased. We assessed the expression of cuproptosis-related genes (CRGs) across TCGA and validated our findings using the GEO data. Consensus clustering divided esophageal cancer (ESCA) patients into two clusters based on the expression of 7 CRGs. We evaluated the expression of immune checkpoint inhibitor (ICI) targets and calculated the elevated tumor mutational burden (TMB). Weighted gene co-expression network analysis (WGCNA) identified genes associated with the expression of CRGs and immunity. Cluster 1 exhibited increased immune infiltration, higher expression of ICI targets, higher TMB, and a higher incidence of deficiency in mismatch repair-microsatellite instability-high status. WGCNA analysis identified 14 genes associated with the expression of CRGs and immune scores. ROC analysis revealed specific hub genes with strong predictive capabilities. The expression levels of SLC6A3, MITD1, and PDHA1 varied across different pathological stages; CCS, LIPT2, PDHB, and PDHA1 showed variation in response to radiation therapy; MITD1 and PDHA1 exhibited differences related to the pathological M stages of ESCA. CRGs influence the immune contexture and can potentially transform cold tumors into hot tumors in ESCA patients.