头颈鳞状细胞癌（HNSCC）是一种异质性恶性肿瘤，由于频繁的治疗失败和明显的治疗耐药性，它仍然是临床治疗中的重大挑战。虽然代谢失调似乎是这种情况下的一个关键因素，但缺乏对代谢性 HNSCC 状况及其对临床结果影响的全面分析。本研究利用来自四个独立临床队列的转录组数据来研究 HNSCC 的代谢异质性并定义基于代谢途径的亚型 (MPS)。在 HPV 阴性 HNSCC 中，发现了 MPS1 和 MPS2，而 MPS3 在 HPV 阳性病例中丰富。 MPS 分类与辅助放（化疗）治疗后的临床结果相关，其中 MPS1 始终表现出最高的治疗失败风险。 MPS1 的独特特征是聚糖（特别是软骨素/硫酸皮肤素）代谢基因的上调。免疫组织化学和预质谱成像分析在代谢物水平证实了这一点。组织学背景和单细胞 RNA 测序数据确定恶性细胞是关键贡献者。在全球范围内，MPS1 的特点是具有与疾病侵袭性增加相关的独特转录组景观，其特征是与上皮间质转化、免疫信号传导、癌症干性、肿瘤微环境组装和致癌信号传导相关的基序。这转化为独特的组织学外观，其特征是广泛的细胞外基质重塑、丰富的纺锤形癌症相关成纤维细胞以及紧密交织的恶性细胞和基质细胞群。来自原位异种移植的概念验证数据在组织学和转录组水平上复制了 MPS 表型。总之，本研究介绍了基于代谢途径的 HNSCC 分类，将富含聚糖代谢的 MPS1 确定为最具挑战性的亚组，需要替代治疗策略。© 2024。作者。

Head and Neck Squamous Cell Carcinoma (HNSCC) is a heterogeneous malignancy that remains a significant challenge in clinical management due to frequent treatment failures and pronounced therapy resistance. While metabolic dysregulation appears to be a critical factor in this scenario, comprehensive analyses of the metabolic HNSCC landscape and its impact on clinical outcomes are lacking. This study utilized transcriptomic data from four independent clinical cohorts to investigate metabolic heterogeneity in HNSCC and define metabolic pathway-based subtypes (MPS). In HPV-negative HNSCCs, MPS1 and MPS2 were identified, while MPS3 was enriched in HPV-positive cases. MPS classification was associated with clinical outcome post adjuvant radio(chemo)therapy, with MPS1 consistently exhibiting the highest risk of therapeutic failure. MPS1 was uniquely characterized by upregulation of glycan (particularly chondroitin/dermatan sulfate) metabolism genes. Immunohistochemistry and pilot mass spectrometry imaging analyses confirmed this at metabolite level. The histological context and single-cell RNA sequencing data identified the malignant cells as key contributors. Globally, MPS1 was distinguished by a unique transcriptomic landscape associated with increased disease aggressiveness, featuring motifs related to epithelial-mesenchymal transition, immune signaling, cancer stemness, tumor microenvironment assembly, and oncogenic signaling. This translated into a distinct histological appearance marked by extensive extracellular matrix remodeling, abundant spindle-shaped cancer-associated fibroblasts, and intimately intertwined populations of malignant and stromal cells. Proof-of-concept data from orthotopic xenotransplants replicated the MPS phenotypes on the histological and transcriptome levels. In summary, this study introduces a metabolic pathway-based classification of HNSCC, pinpointing glycan metabolism-enriched MPS1 as the most challenging subgroup that necessitates alternative therapeutic strategies.© 2024. The Author(s).