Myeloid-derived suppressor cells confer stemness to esophageal cancer cells through the HNF1A/CXCL1 signaling axis

Abstract

Our previous work established that myeloid-derived suppressor cells (MDSCs) were abundant in human esophageal squamous cell carcinoma (ESCC) and correlated with adverse prognosis. Yet their direct, T cell-independent impact on tumor propagation remains undefined. Here, we show that MDSCs accelerate ESCC growth in both immunocompetent and T cell-deficient mice, indicating an intrinsic tumor-promoting program. Anti-Gr1-mediated MDSC depletion or IL-1β neutralization reduced intratumoral HNF1A expression, blunted CXCL1 promoter activity and down-regulated the stemness transcription factors Oct4, Nanog and Sox9. Deletion of HNF1A in tumor cells abolished MDSC-driven expansion of cancer stem cells (CSCs) and abrogated tumor initiation, whereas exogenous IL-1β reinstated CSC frequencies. Thus, MDSC-derived IL-1β licenses an HNF1A–CXCL1 axis that sustains CSC properties independently of adaptive immunity. Targeting this pathway may complement T cell-focused therapies in ESCC. Graphical abstract Myeloid-derived suppressor cells license stem-like properties in esophageal squamous cell carcinoma via HNF1A-driven CXCL1 signaling and predict poor prognosis.