Metabolic reprogramming is a hallmark of cancer. In addition to metabolic alterations in the tumor cells, multiple other metabolically active cell types in the tumor microenvironment (TME) contribute to the emergence of a tumor-specific metabolic milieu. Here, we defined the metabolic landscape of the TME during progression of head and neck squamous cell carcinoma (HNSCC) by performing single-cell RNA sequencing (scRNA-seq) on 26 human patient specimens, including normal tissue, pre-cancerous lesions, early-stage cancer, advanced-stage cancer, lymph node metastases, and recurrent tumors. The analysis revealed substantial heterogeneity at the transcriptional, developmental, metabolic, and functional levels in different cell types. SPP1+ macrophages were identified as a pro-tumor and pro-metastatic macrophage subtype with high fructose and mannose metabolism, which was further substantiated by integrative analysis and validation experiments. An inhibitor of fructose metabolism reduced the proportion of SPP1+ macrophages, reshaped the immunosuppressive TME, and suppressed tumor growth. In conclusion, this work delineated the metabolic landscape of HNSCC at a single-cell resolution and identified fructose metabolism as a key metabolic feature of a pro-tumor macrophage subpopulation.

中文翻译：

---

单细胞分析揭示头颈鳞状细胞癌进展过程中肿瘤微环境的代谢异质性和可塑性

代谢重编程是癌症的一个标志。除了肿瘤细胞的代谢改变外，肿瘤微环境（TME）中多种其他代谢活跃的细胞类型也有助于肿瘤特异性代谢环境的出现。在这里，我们通过对 26 名人类患者样本（包括正常组织、癌前病变、早期病变）进行单细胞 RNA 测序 (scRNA-seq) 来定义头颈鳞状细胞癌 (HNSCC) 进展过程中 TME 的代谢状况。 -阶段癌症、晚期癌症、淋巴结转移和复发性肿瘤。分析揭示了不同细胞类型在转录、发育、代谢和功能水平上存在显着的异质性。 SPP1+巨噬细胞被鉴定为具有高果糖和甘露糖代谢的促肿瘤和促转移巨噬细胞亚型，并通过综合分析和验证实验进一步证实。果糖代谢抑制剂可减少 SPP1+ 巨噬细胞的比例，重塑免疫抑制性 TME，并抑制肿瘤生长。总之，这项工作以单细胞分辨率描绘了 HNSCC 的代谢图谱，并将果糖代谢确定为促肿瘤巨噬细胞亚群的关键代谢特征。