Glucokinase Regulatory Protein (GCKR) Links Metabolic Reprogramming With Immune Exclusion: Insights From a Pan‐Cancer Analysis and Gastric Cancer Validation

Glucokinase regulatory protein (GCKR) is a metabolic regulator implicated in glucose homeostasis, but its genetic and functional roles in cancer remain poorly understood. Through integrated pan-cancer 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-cold phenotype characterized by diminished cytotoxic T cell infiltration, impaired antigen presentation, and metabolic reprogramming. Spatial transcriptomics and single-cell analyses highlighted compartment-specific heterogeneity and links with cancer-associated 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- and expression-driven biomarker that connects metabolic regulation with immune remodeling, offering translational value for prognosis and precision therapy in gastric cancer.