Data from Single-Cell Analyses Reveal the Metabolic Heterogeneity and Plasticity of the Tumor Microenvironment during Head and Neck Squamous Cell Carcinoma Progression

<div>Abstract<p>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 the progression of head and neck squamous cell carcinoma (HNSCC) by performing single-cell RNA sequencing on 26 human patient specimens, including normal tissue, precancerous 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. <i>SPP1</i>⁺ macrophages were identified as a protumor and prometastatic 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 <i>SPP1</i>⁺ 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 protumor macrophage subpopulation.</p><p><b>Significance:</b> Fructose and mannose metabolism is a metabolic feature of a protumor and prometastasis macrophage subtype and can be targeted to reprogram macrophages and the microenvironment of head and neck squamous cell carcinoma.</p></div>