High glucose confers senescence resistance via GLUT1 epigenetic rewiring to blunt immunotherapy responses in esophageal squamous cell carcinoma

Dong, J.-X.; Zhou, J.; Hao, J.-J.; Kong, S.; Yin, C.; Wei, D.-D.; Wang, F.; Ma, J.; Fang, J.; Zhang, Y.-W.; Pan, H.; Wei, W.-Q.; Wang, M.; Ma, K.; Jiang, Y.; Jiang, Y.-Y.

doi:10.64898/2026.07.15.738372

bioRxiv · 10.64898/2026.07.15.738372

High glucose confers senescence resistance via GLUT1 epigenetic rewiring to blunt immunotherapy responses in esophageal squamous cell carcinoma

Dong, J.-X.·Zhou, J.·Hao, J.-J.·Kong, S.·Yin, C.·Wei, D.-D.·Wang, F.·Ma, J.·Fang, J.·Zhang, Y.-W.·Pan, H.·Wei, W.-Q.·Wang, M.·Ma, K.·Jiang, Y.·Jiang, Y.-Y.

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Abstract

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 (-PD1) therapy. Importantly, dietary glucose restriction exhibits equivalent antitumor efficacy to GLUT1 inhibition when combined with -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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=188 HEIGHT=200 SRC="FIGDIR/small/738372v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@c2c5d5org.highwire.dtl.DTLVardef@14a34c7org.highwire.dtl.DTLVardef@cf05e4org.highwire.dtl.DTLVardef@18bc354_HPS_FORMAT_FIGEXP M_FIG C_FIG SHORT SUMMARYDong 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.

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Dong, J.-X., Zhou, J., Hao, J.-J., Kong, S., Yin, C., Wei, D.-D., Wang, F., Ma, J., Fang, J., Zhang, Y.-W., Pan, H., Wei, W.-Q., Wang, M., Ma, K., Jiang, Y., Jiang, Y.-Y.. 2026-07-16. High glucose confers senescence resistance via GLUT1 epigenetic rewiring to blunt immunotherapy responses in esophageal squamous cell carcinoma. https://doi.org/10.64898/2026.07.15.738372

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