<p>Head and neck squamous cell carcinoma (HNSCC) exhibits a poor prognosis, particularly in advanced stages characterized by high recurrence and metastasis rates. This study investigates the role of lactate metabolism in HNSCC, aiming to develop a prognostic model to predict immunotherapy outcomes. Genomic and clinical data from The Cancer Genome Atlas and Gene Expression Omnibus databases were analyzed, focusing on 233 lactate metabolism-related genes (LMGs). Differential expression and Cox regression analyses identified two significant prognostic genes: glycogen phosphorylase L (<i>PYGL</i>) and solute carrier family 16 member 3 (<i>SLC16 A3</i>, encoding MCT4). A lactate risk score (LRS) model constructed from these genes demonstrated robust predictive accuracy across multiple validation datasets. Multivariate analysis validated LRS as an independent prognostic factor, and a nomogram integrating LRS with clinical parameters further improved survival prediction accuracy. Immune infiltration analyses revealed distinct immune landscapes between high- and low-risk groups. Elevated levels of CD4 naïve T cells, resting NK cells, M0 macrophages, and activated mast cells characterized the high-risk group, whereas naive B cells, plasma cells, CD8 T cells, T follicular helper cells, regulatory T cells, gamma delta T cells, resting dendritic cells, resting mast cells, and eosinophils predominated in the low-risk group. Additionally, molecular docking suggested valproic acid as a potential inhibitor of MCT4. Immunohistochemical analyses showed increased PYGL and MCT4 expression correlated with advanced tumor stage, alongside decreased expression of CXCL9 and CXCL10. These findings highlight the critical role of lactate metabolism in HNSCC progression and immunotherapy resistance, identifying PYGL and MCT4 as promising therapeutic targets.</p>