We integrated single-cell RNA sequencing data from seven datasets (192 ESCC patients, >440k cells) and spatial transcriptomics to delineate the tumor microenvironment (TME) landscape of esophageal squamous cell carcinoma (ESCC) during progression and immunotherapy response. B-lineage cells decreased with tumor progression but accumulated in immunotherapy-resistant cases. Resistant tumors harbored a malignant subpopulation with elevated cholesterol biosynthesis. Spatial and communication analyses revealed that these cholesterol-biosynthetic tumor cells interacted with germinal center B cells in tertiary lymphoid structures. Mechanistically, tumor-derived MIF disrupted B cell immunity by competing with CXCL12–CXCR4 signaling through MIF–CXCR4 binding.

MIF-expressing tumor cells mediate immunotherapeutic resistance in esophageal squamous cell carcinoma

Jing Song¹, Xiaomei Song², Yue Xie¹, Hong Guo² , Yupeng Cun¹