Differential GLUT1 Expression on Lymphocytes Drives Immune Evasion in the Tumor Microenvironment

Diabetes mellitus (DM), a metabolic disorder affecting over 500 million individuals globally, is characterized by chronic hyperglycemia and immune dysregulation. While Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing β-cells, Type 2 diabetes (T2D) arises from insulin resistance and chronic inflammation. Recent advances in immunometabolism have highlighted the pivotal role of glucose transporters (GLUTs) in regulating lymphocyte function, bridging metabolic demand and immune activity. This review synthesizes current evidence on the contributions of GLUT1, GLUT3, and GLUT4 in T cells, B cells, and innate lymphocytes to diabetic pathogenesis. We discuss how GLUT-driven glycolysis fuels autoreactive T cells in T1D and sustains adipose tissue inflammation in T2D, while dysfunctional regulatory T cells (Tregs) fail to suppress immune responses due to altered GLUT expression. Emerging therapies targeting lymphocyte Gluts including GLUT1 inhibitors, metabolic modulators, and nanoparticle-based delivery systemsare evaluated for their potential to restore immune balance. Controversies, such as the compensatory roles of non-GLUT transporters and conflicting preclinical outcomes, are critically addressed. By integrating mechanistic insights with clinical data, this review underscores the dual role of lymphocyte GLUTs as both drivers of pathology and therapeutic targets, offering a roadmap for future research in precision immunometabolism.