Metabolic Programming of Tumor-Associated Macrophages in Head and Neck Squamous Cell Carcinoma: Implications for Innate Immunity and Therapeutic Response

Head and neck squamous cell carcinoma (HNSCC) develops within a chronically inflamed and metabolically constrained tumor microenvironment that profoundly shapes innate immune function. Tumor-associated macrophages (TAMs) are abundant in HNSCC and display marked plasticity, yet predominantly acquire immunosuppressive states that promote tumor progression and therapeutic resistance. Traditional M1/M2 polarization models fail to capture this dynamic behavior. Emerging evidence instead identifies metabolic reprogramming as a central regulator of macrophage function in cancer. Hypoxia, nutrient limitation, extracellular acidification, and tumor-derived metabolites such as lactate and lipids rewire macrophage metabolism, directly influencing inflammatory signaling and immune suppression. This review integrates recent advances in immunometabolism to examine how metabolic adaptations govern macrophage innate functions in HNSCC and highlights therapeutic opportunities targeting macrophage metabolism to overcome immune resistance.