Metabolic heterogeneity plays a central role in sustaining uncontrolled cancer cell proliferation and shaping the tumor microenvironment (TME), which significantly compromises the clinical outcomes and responses to therapy in head and neck squamous cell carcinoma (HNSCC) patients. This highlights the urgent need to delineate the intrinsic heterogeneity and biological roles of metabolic vulnerabilities to advance precision oncology. The metabolic heterogeneity of malignant cells was identified using single-cell RNA sequencing (scRNA-seq) profiles and validated through bulk transcriptomes. Serine–glycine-one-carbon (SGOC) metabolism was screened out to be responsible for the aggressive malignant properties and poor prognosis in HNSCC patients. A 4-SGOC gene prognostic signature, constructed by LASSO-COX regression analysis, demonstrated good predictive performance for overall survival and therapeutic responses. Patients in the low-risk group exhibited greater infiltration of exhausted CD8⁺ T cells, and demonstrated better clinical outcomes after receiving immunotherapy and chemotherapy. Conversely, high-risk patients exhibited characteristics of cold tumors, with enhanced IMPDH1-mediated purine biosynthesis, resulting in poor responses to current therapies. IMPDH1 emerged as a potential therapeutic metabolic target. Treatment with IMPDH inhibitors effectively suppressed HNSCC cell proliferation and metastasis and induced apoptosis in vitro and in vivo by triggering GTP-exhaustion nucleolar stress. Our findings underscore the metabolic vulnerabilities of HNSCC in facilitating accurate patient stratification and individualized precise metabolic-targeted treatment.

代谢异质性在维持不受控制的癌细胞增殖和塑造肿瘤微环境（TME）方面发挥着核心作用，这显着影响了头颈鳞状细胞癌（HNSCC）患者的临床结果和治疗反应。这凸显了迫切需要描述代谢脆弱性的内在异质性和生物学作用，以推进精准肿瘤学。使用单细胞 RNA 测序 (scRNA-seq) 谱鉴定恶性细胞的代谢异质性，并通过批量转录组进行验证。丝氨酸-甘氨酸一碳（SGOC）代谢被筛选出是导致 HNSCC 患者侵袭性恶性特性和不良预后的原因。通过 LASSO-COX 回归分析构建的 4-SGOC 基因预后特征显示出对总体生存率和治疗反应的良好预测性能。低风险组的患者表现出更多的耗尽的CD8 ⁺ T细胞浸润，并且在接受免疫治疗和化疗后表现出更好的临床结果。相反，高危患者表现出冷肿瘤的特征，IMPDH1介导的嘌呤生物合成增强，导致对当前疗法的反应较差。 IMPDH1 成为潜在的治疗代谢靶点。 IMPDH抑制剂治疗可有效抑制HNSCC细胞增殖和转移，并通过触发GTP耗竭核仁应激在体外和体内诱导细胞凋亡。我们的研究结果强调了 HNSCC 在促进准确的患者分层和个体化精确代谢靶向治疗方面的代谢脆弱性。