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In this study, we show that GSNOR deficiency in tumors is associated with poor prognostic histopathological features and poor survival in patients with colorectal cancer (CRC). GSNOR\u2010low tumors were characterized by an immunosuppressive microenvironment with exclusion of cytotoxic CD8<jats:sup>+<\/jats:sup> T cells. Notably, GSNOR\u2010low tumors exhibited an immune evasive proteomic signature along with an altered energy metabolism characterized by impaired oxidative phosphorylation (OXPHOS) and energetic dependence on glycolytic activity. CRISPR\u2010Cas9\u2010mediated generation of GSNOR gene knockout (KO) CRC cells confirmed <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> that GSNOR\u2010deficiency conferred higher tumorigenic and tumor\u2010initiating capacities. Moreover, GSNOR\u2010KO cells possessed enhanced immune evasive properties and resistance to immunotherapy, as revealed following xenografting them into humanized mouse models. Importantly, GSNOR\u2010KO cells were characterized by a metabolic shift from OXPHOS to glycolysis to produce energy, as indicated by increased lactate secretion, higher sensitivity to 2\u2010deoxyglucose (2DG), and a fragmented mitochondrial network. Real\u2010time metabolic analysis revealed that GSNOR\u2010KO cells operated close to their maximal glycolytic rate, as a compensation for lower OXPHOS levels, explaining their higher sensitivity to 2DG. Remarkably, this higher susceptibility to glycolysis inhibition with 2DG was validated in patient\u2010derived xenografts and organoids from clinical GSNOR\u2010low tumors. In conclusion, our data support the idea that metabolic reprogramming induced by GSNOR deficiency is an important mechanism for tumor progression and immune evasion in CRC and that the metabolic vulnerabilities associated with the deficiency of this denitrosylase can be exploited therapeutically. \u00a9 2023 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6080","type":"journal-article","created":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T09:20:57Z","timestamp":1680686457000},"page":"261-275","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Metabolic shift underlies tumor progression and immune evasion in S\u2010nitrosoglutathione reductase\u2010deficient 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