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Through integrated pan\u2010cancer multiomics and experimental analyses, we mapped the expression and mutational landscape of GCKR with a focus on gastric cancer. GCKR expression was downregulated in most tumors but upregulated in subsets such as kidney renal papillary carcinoma (KIRP) and lung adenocarcinoma (LUAD). Genomic profiling revealed recurrent alterations, with the highest mutation frequencies observed in sarcoma (SARC) and uterine corpus endometrial carcinoma (UCEC), and missense mutations representing the predominant variant type, particularly in breast cancer (BRCA). Functionally, reduced GCKR expression in gastric cancer was associated with an immune\u2010cold phenotype characterized by diminished cytotoxic T cell infiltration, impaired antigen presentation, and metabolic reprogramming. Spatial transcriptomics and single\u2010cell analyses highlighted compartment\u2010specific heterogeneity and links with cancer\u2010associated fibroblasts and macrophages. Clinically, low GCKR expression predicted poorer survival and reduced immunotherapy benefit, while higher expression indicated selective sensitivity to MEK inhibitors including refametinib and PD0325901. These findings define GCKR as both a mutation\u2010 and expression\u2010driven biomarker that connects metabolic regulation with immune remodeling, offering translational value for prognosis and precision therapy in gastric cancer.<\/jats:p>","DOI":"10.1155\/humu\/4240223","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T10:58:07Z","timestamp":1762340287000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Glucokinase Regulatory Protein (GCKR) Links Metabolic Reprogramming With Immune Exclusion: Insights From a Pan\u2010Cancer Analysis and Gastric Cancer 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