Metabolic Reprogramming and Tumor Immune Evasion in Oral Cancer from Molecular Mechanisms to Precision Therapeutic Strategies

Abstract

Oral cancer remains a major malignancy of the head and neck region. Oral squamous cell carcinoma represents the predominant histological form and is characterized by substantial metabolic heterogeneity. Increasing evidence indicates that metabolic alterations are not simply secondary consequences of malignant transformation. It can actively support the tumor progression by allowing cancer cells to adapt to changes in oxygen availability and nutrient supply. Glucose metabolism is extensively altered in oral cancer. Increased glycolysis and lactate production provide energy and biosynthetic intermediates required for tumor growth. Glutamine metabolism was also contributed to the nucleotide synthesis and antioxidant defense. Alterations in lipid metabolism further supports the membrane formation and tumor cell proliferation. These metabolic changes occur within a complex tumor microenvironment containing cancer associated fibroblasts, immune cells, endothelial cells and extracellular matrix components. Metabolic exchange between these populations can modify tumor behavior and promote immune suppression. Recent spatial transcriptomic studies have shown that metabolically active regions of oral squamous cell carcinoma are associated with increased regulatory T cell infiltration and TGF β activity. Lactate produced by tumor cells can also alter fibroblast and macrophage functions. Such findings indicate that metabolic plasticity is a shared feature of both tumor cells and their surrounding microenvironment. This review discusses the metabolic alterations associated with oral cancer initiation mand progression. Particular attention is given to glucose metabolism, glutamine utilization, lipid metabolism, hypoxia, lactate signaling and metabolic interactions between cancer cells and stromal and immune populations. The potential relationship between metabolic plasticity and invasion, metastasis, treatment resistance and clinical outcome is also discussed. Understanding these metabolic interactions may provide new opportunities for developing therapeutic strategies that target both tumor metabolism and the surrounding microenvironment.