Compartment-specific GLUT1 patterns in colorectal liver metastases: invasive-margin GLUT1 associates with outcome in solitary disease

BACKGROUND: Colorectal liver metastases (CRLM) are a major cause of cancer-related deaths. Glucose transporter 1 (GLUT1) is a key mediator of glycolytic metabolism in malignant and immune cells; however, the prognostic relevance of compartment-specific GLUT1 patterns in CRLM remains undefined. We hypothesized that spatial GLUT1 expression at the tumor-liver interface may reflect clinically relevant microenvironmental biology. METHODS: We retrospectively analyzed data of 192 patients who underwent curative-intent resection for CRLM (75 solitary; 117 multiple). GLUT1 expression was assessed by immunohistochemistry in the tumor tissue (Tu) and infiltration margin (Im) and was correlated with overall survival using Cox regression. Double immunofluorescence for CD8 and GLUT1 was performed for qualitative visualization at the infiltration margin. In an exploratory subset (n = 5), flow cytometry and in vitro killing assays were conducted on GLUT1⁺ versus GLUT1⁻ CD8⁺ tumor-infiltrating lymphocytes (TILs). RESULTS: Tumoral GLUT1 correlated with Ki67 (Spearman's ρ = 0.31, p = 0.003) but was not independently associated with overall survival in the main cohort (multivariable HR 1.183, 95% CI 0.74-1.90; p = 0.485). In the main cohort, capsule presence remained strongly associated with improved survival (HR 0.35, 95% CI 0.21-0.58; p < 0.001). In contrast, high invasive-margin GLUT1 was independently associated with improved survival in the predefined solitary cohort (HR 0.379, 95% CI 0.18-0.81; p = 0.012). Double immunofluorescence demonstrated the qualitative co-localization of the GLUT1 signal with CD8⁺ cells at the infiltration margin. In exploratory assays (n = 5), flow cytometry suggested GLUT1 enrichment in CD8⁺ terminally differentiated effector memory T cells re-expressing CD45RA (TEMRA), and GLUT1⁺ TIL fractions showed higher in vitro tumor cell killing compared with GLUT1⁻ cells. CONCLUSION: GLUT1 shows compartment- and context-dependent associations in the CRLM. While tumor-core GLUT1 is linked to proliferative activity, invasive-margin GLUT1 is associated with favorable outcomes in solitary metastases. Immunofluorescence and functional data provide hypothesis-generating context and warrant validation with quantitative spatial immune profiling and independent cohorts.