Glycolysis Inhibition Restores Immune Sensitivity in GSNOR–Deficient Colorectal Cancer

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S-nitrosoglutathione reductase (GSNOR) is increasingly recognized as a tumor suppressor, and we have recently reported that its deficiency drives an aggressive and immune-evasive phenotype in colorectal cancer (CRC). However, the mechanisms linking GSNOR loss to immune escape remain incompletely understood. In this study, we uncover a previously unrecognized connection between metabolic reprogramming and immune escape in GSNOR-deficient CRC and identify a therapeutic vulnerability that can be exploited to restore immune responsiveness. A comprehensive analysis of 137 clinical CRC samples revealed that GSNOR-deficient tumors exhibit high-grade tumor budding, an established marker of poor prognosis, and reduced CD4 + and CD8 + T-cell infiltration, consistent with an immunosuppressive tumor microenvironment. Integrating transcriptomic, immunohistochemical, and single–cell RNA-sequencing data, we demonstrate that GSNOR-deficient tumors undergo a striking metabolic reprogramming toward glycolytic dependence, with elevated lactate production contributing to T-cell exclusion. Based on these findings, we show that pharmacologic glycolysis inhibition with 2-deoxyglucose reverses immune resistance in GSNOR-knockout models, enhancing CD8 + T-cell infiltration and sensitizing tumors to anti–PD-1 therapy both in vitro and in vivo. Notably, this is the first demonstration that metabolic intervention can restore immune sensitivity in GSNOR-deficient CRC. Our results identify GSNOR expression as a predictive biomarker for metabolic-immune combinatorial strategies and support the clinical translation of 2-deoxyglucose plus anti–PD-1 as a precision immunotherapy approach for this high-risk CRC phenotype.

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