Through integrative analysis of spatial transcriptomics in two paired pre-/post-treatment ESCC specimens (n = 2 patients) combined with single-cell RNA-seq (scRNA-seq) data from ~440,000 high-quality cells, we identified that MIF-expressing tumor cells competitively disrupted CXCL12-CXCR4 signaling in GC B dark-zone cells via direct MIF-CXCR4 interactions, thereby impairing GC reactions within the TME. Here, CXCR4 is linked to esophageal squamous cell carcinoma.