EZH2 elicits CD8⁺ T-cell desert in esophageal squamous cell carcinoma via suppressing CXCL9 and dendritic cells

CD8⁺ T cell spatial distribution in the context of tumor microenvironment (TME) dictates the immunophenotypes of tumors, comprised of immune-infiltrated, immune-excluded and immune-desert, discriminating "hot" from "cold" tumors. The infiltration of cytotoxic CD8⁺ T cells is associated with favorable therapeutic response. Hitherto, the immunophenotypes of esophageal squamous cell carcinoma (ESCC) have not yet been comprehensively delineated. Herein, we comprehensively characterized the immunophenotypes of ESCC and identified a subset of ESCC, which was defined as cold tumor and characterized with CD8⁺ T cell-desert TME. However, the mechanism underlying the defect of CD8⁺ T cells in TME is still pending. Herein, we uncovered that tumor cell-intrinsic EZH2 with high expression was associated with the immunophenotype of immune-desert tumors. Targeted tumor cell-intrinsic EZH2 rewired the transcriptional activation of CXCL9 mediated by NF-κB and concomitantly reinvigorated DC maturation differentiation via inducing the reduction of VEGFC secretion, thereby enhancing the infiltration of cytotoxic CD8⁺ T cells into TME and inhibiting tumor immune evasion. Our findings identify EZH2 as a potential therapeutic target and point to avenues for targeted therapy applied to patients with ESCC characterized by CD8⁺ T cell-desert tumors.