HDGF induces inflammatory cancer-associated fibroblast formation through ENO1-mediated glycolytic reprogramming in esophageal squamous-cell carcinoma.

Abstract

Inflammatory cancer-associated fibroblasts (iCAFs) are a highly plastic stromal population that critically shapes tumor progression, immunosuppression, and therapeutic response in esophageal squamous-cell carcinoma (ESCC). Epithelial-intrinsic programs are increasingly recognized as key determinants of fibroblast reprogramming within the tumor microenvironment, yet the underlying mechanisms remain incompletely understood. Here, we identified hepatoma-derived growth factor (HDGF) as a pivotal epithelial-intrinsic regulator that drives iCAF formation in ESCC. Mechanistically, nuclear HDGF functioned as a transcriptional activator by directly binding the ENO1 promoter, thereby upregulating the expression of the glycolytic enzyme enolase 1, enhancing aerobic glycolysis, and promoting lactate secretion from tumor cells. Tumor-derived lactate was subsequently taken up by CAFs and induced histone H4 lysine 12 lactylation (H4K12la), which epigenetically activated NF-κB signaling and promoted iCAF formation. Functionally, HDGF-induced iCAFs promoted tumor progression through activation of the IL-6/JAK1/STAT3 axis and established an immunosuppressive microenvironment characterized by increased recruitment of regulatory T cells and reduced infiltration of CD8+ T cells, thereby facilitating immune evasion. Therapeutically, blockade of ENO1 effectively disrupted the glycolysis-lactylation cascade, markedly suppressing tumor growth and iCAF formation in vivo. Moreover, ENO1 inhibition reprogrammed the immunosuppressive tumor microenvironment and significantly enhanced the efficacy of anti-PD-1 therapy. Collectively, our findings reveal an HDGF/ENO1/H4K12la/iCAF axis that links tumor metabolic reprogramming, stromal inflammatory activation, and immunosuppression in ESCC, identifying this axis as a promising therapeutic target for overcoming immunotherapy resistance.