Targeting glutaminase (GLS) to suppress CXCL8 secretion and sensitize esophageal squamous cell carcinoma to immunotherapy.

Immune checkpoint inhibitor (ICI) resistance remains a major challenge in esophageal squamous cell carcinoma (ESCC). This study investigates the role of glutaminase (GLS) in modulating the tumor immune microenvironment and its impact on immunotherapy response. Bioinformatic analysis of TCGA data revealed an inverse correlation between GLS expression and CD8+ T cell infiltration. In ESCC clinical specimens, high GLS expression correlated with elevated CXCL8 levels and reduced CD8+ T cell infiltration. Mechanistically, our data support an association between GLS expression and increased CXCL8 transcription, accompanied, at least in part, by HAT-dependent enhancement of H3K27 acetylation at the CXCL8 promoter region. In advanced ESCC patients receiving immunochemotherapy, high tumoral GLS expression was associated with significantly shorter progression-free survival. In vitro and in vivo functional studies showed that GLS knockdown in ESCC cells was associated with enhanced T-cell effector cytokine secretion, increased tumor infiltration of CD8+ T cells, and greater tumor suppression when combined with anti-PD-1 therapy in a humanized mouse model. Importantly, exogenous CXCL8 supplementation partially reversed the increased Granzyme B and IFNγ secretion induced by GLS knockdown in the co-culture system, supporting a functional role for CXCL8 in GLS-associated immune suppression. These results support a model in which GLS contributes to an immunosuppressive microenvironment in ESCC, at least in part through epigenetic upregulation of CXCL8. These findings support further investigation of GLS targeting as a potential strategy to improve immunotherapy response in ESCC.