Background <p>Non-small cell lung cancer (NSCLC) is a highly heterogeneous malignancy characterized by altered glucose metabolism. Integration of PET/CT radiomics with glucose metabolism-related genomic signatures could provide a more comprehensive approach for prognosis and treatment guidance.</p> Methods <p>Radiomics features were extracted from PET/CT images of 156 NSCLC patients from The Cancer Imaging Archive (TCIA) database, and glucose metabolism-related gene signatures were obtained from TCGA and GEO databases. We developed a multimodal radiogenomics prognostic model (RGC-score) using least absolute shrinkage and selection operator (LASSO) regression, combining PET/CT radiomics, glucose metabolism-related genes (GMR-genes). Functional enrichment analysis, immune infiltration assessment, and drug sensitivity analysis were performed to investigate the biological significance of glucose metabolism-related genes (GMR-genes).</p> Results <p>The RGC-score model effectively stratified NSCLC patients into distinct high- and low-risk groups with significant differences in survival outcomes (<i>P &lt; </i>0.001), demonstrating excellent predictive performance (1-year AUC = 0.907, 5-year AUC = 0.968).GMR-genes are mainly involved in the process of metabolic remodeling of tumors, which is closely related to the immune microenvironment (especially CD8⁺ T cell infiltration) and immune checkpoint molecule expression. Additionally, significant differences in drug sensitivity were identified between glucose metabolism subtypes.</p> Conclusion <p>The RGC-score robustly predicts NSCLC prognosis and informs metabolic-immune interactions for personalized therapy. Limitations include the retrospective design and modest validation cohort size, necessitating prospective multicenter trials.</p>