Abstract
Nasopharyngeal carcinoma (NPC) exhibits a heterogeneous tumor immune microenvironment (TIME) shaped by chemokine signaling, yet the functional roles of tumor-derived chemokines remain elusive. This study integrates single-cell RNA sequencing (scRNA-seq) of NPC tissues with validation in 109 primary patient samples, revealing CXCL10 and CCL20 as tumor-secreted chemokines localized to distinct malignant epithelial subpopulations with antagonistic roles. CXCL10 correlates with prolonged progression-free survival (PFS) and enriches an immune-active TIME by recruiting CD8+ T cells and CD20+ B cells, whereas CCL20 associates with poor prognosis and immunosuppression through preferential recruitment of regulatory T cells (Tregs). Functional validation via in vitro chemotaxis assays and in vivo xenograft models demonstrates that CXCL10 overexpression suppresses tumor growth by enhancing effector immune cell infiltration, while CCL20 promotes Treg accumulation without impeding tumor progression. Mechanistically, Tregs in NPC exhibit elevated expression of co-inhibitory molecules (CTLA4, TIGIT) and engage B cells via CTLA4-CD86 signaling, potentially impairing antigen presentation. Multi-omics analysis of bulk RNA-seq, immunohistochemistry, and cell-cell communication further delineates the antagonistic interplay between CXCL10-driven immune activation and CCL20-mediated immunosuppression. Our findings establish CXCL10 and CCL20 as dual regulators of TIME polarization in NPC, offering prognostic biomarkers and therapeutic targets to rebalance antitumor immunity.