Abstract
<jats:title>Abstract</jats:title> <jats:p>Therapeutic resistance and undefined predictive biomarkers severely hinder the clinical popularization of immunotherapy in esophageal squamous cell carcinoma (ESCC). Herein, we identify the glucose transporter 1 (GLUT1) as a critical determinant of immunotherapy resistance. Elevated expression of GLUT1 correlates with poor immunotherapy response and unfavorable prognosis in ESCC patients. GLUT1 deletion or inhibition enhances CD8⁺ T cell infiltration and cytotoxicity, and sensitizes ESCC tumors to anti-PD-1 (α-PD1) therapy. Importantly, dietary glucose restriction exhibits equivalent antitumor efficacy to GLUT1 inhibition when combined with α-PD1. Mechanistically, GLUT1 establishes a positive feedback loop with HAT1 and FOXM1, which epigenetically remodels chromatin accessibility to suppress tumor cell senescence, thereby impeding CD8⁺ T cell-mediated antitumor immunity. Our findings highlight GLUT1 as a predictive biomarker of immunotherapy resistance and suggest dietary glucose restriction as a viable strategy to potentiate immunotherapy efficacy in ESCC.</jats:p> <jats:sec> <jats:title>Graphical abstract</jats:title> <jats:fig id="ufig1" position="float" orientation="portrait" fig-type="figure"> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="738372v1_ufig1" position="float" orientation="portrait"/> </jats:fig> </jats:sec> <jats:sec> <jats:title>SHORT SUMMARY</jats:title> <jats:p>Dong et al. identify glucose transporter 1 (GLUT1) as a predictor of poor response to immunotherapy in esophageal squamous cell carcinoma. GLUT1 promotes immune evasion by forming a positive feedback loop with the HAT1/FOXM1 anti-senescence axis, thereby epigenetically remodeling chromatin accessibility. GLUT1 inhibition or dietary glucose restriction restores CD8⁺ T-cell-mediated antitumor immunity and improves the efficacy of anti-PD-1 therapy in preclinical models.</jats:p> </jats:sec>