Jiang Huanyu, Zhou Lijuan, Zhang Haidong, Gong Shanchun, Yu Zhenkun
School of Medicine, Southeast University, 87 Dingjiaqiao, Hunan Road, Nanjing, 210009, Jiangsu, China.
Department of Otolaryngology Head and Neck Surgery, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210019, Jiangsu, China.
Discov Oncol. 2025 May 24;16(1):909. doi: 10.1007/s12672-025-02706-w.
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 (PYGL) and solute carrier family 16 member 3 (SLC16 A3, 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.
头颈部鳞状细胞癌（HNSCC）的预后较差，尤其是在以高复发率和转移率为特征的晚期阶段。本研究调查了乳酸代谢在HNSCC中的作用，旨在建立一个预测免疫治疗结果的预后模型。分析了来自癌症基因组图谱和基因表达综合数据库的基因组和临床数据，重点关注233个与乳酸代谢相关的基因（LMGs）。差异表达分析和Cox回归分析确定了两个显著的预后基因：糖原磷酸化酶L（PYGL）和溶质载体家族16成员3（SLC16A3，编码MCT4）。由这些基因构建的乳酸风险评分（LRS）模型在多个验证数据集中显示出强大的预测准确性。多变量分析验证了LRS是一个独立的预后因素，将LRS与临床参数相结合的列线图进一步提高了生存预测准确性。免疫浸润分析揭示了高风险组和低风险组之间不同的免疫格局。高风险组的特征是CD4幼稚T细胞、静息NK细胞、M0巨噬细胞和活化肥大细胞水平升高，而低风险组中幼稚B细胞、浆细胞、CD8 T细胞、滤泡辅助性T细胞、调节性T细胞、γδ T细胞、静息树突状细胞、静息肥大细胞和嗜酸性粒细胞占主导。此外，分子对接表明丙戊酸是MCT4的潜在抑制剂。免疫组织化学分析显示，PYGL和MCT4表达增加与肿瘤晚期相关，同时CXCL9和CXCL10表达降低。这些发现突出了乳酸代谢在HNSCC进展和免疫治疗耐药中的关键作用，确定PYGL和MCT4为有前景的治疗靶点。
