Spatially resolved multiomics reveals the self-enforcing property of the leading-edge multicellular ecosystem of head and neck cancer

• 成果类型: Article
• 署名作者: Su, Zhi -Fei; Wu, Chen -Zhou; Ding, Hao -Ran; Zhan, Qi; Ba, Yong -Bing; Cheng, Lei; Li, Ji -Yao; Zhou, Xue -Dong; Li, Long -Jiang; Zhang, Li -Xin; Li, Jing; Li, Yi; Ren, Biao
• 署名单位: Sichuan University; Sichuan University; Sichuan University; Sichuan University; Sichuan University; Sichuan University; East China University of Science and Technology; Tianfu Jiangxi Laboratory
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2519474123
• 发表日期: 2026-01-13
• 页码: e2519474123
• 关键词: HNSCC; cancer leading-edge ecosystem; spatial multiomics; cancer invasion; INVASIVE FRONT; metastasis; fibrosis; cells

摘要

Head and neck squamous cell carcinoma (HNSCC) involves aggressive invasion at the tumor-host interface, particularly at the leading edge. However, the mechanisms sustaining this invasive front remain unclear. Here, we performed spatially resolved multiomics profiling to characterize the leading-edge multicellular ecosystem (LEMCE) of HNSCC. We identified a set of twelve autocrine ligands, including TGFB1, ICAM1, and TNC, that support a stable invasive transcriptional state. Impaired fatty acid (FA) degradation in this region enhances autocrine ligands and amplifies proinvasive gene expression. Spatial single-cell analysis revealed that the specific resident cells in the LEMCE, which exhibited increased expression of autocrine ligands and impaired FA degradation, participated in a fibroblast-macrophage-T cell interaction circuit involving MMP1+ fibroblasts and C1QC+/SPP1+ macrophages, followed by interactions between C1QC+ macrophages and cytotoxic T cells. These interactions may contribute to the structural organization and immunosuppressive features of the LEMCE. Therapeutically, targeting this niche via a combination of autocrine cytokine blockade, FA metabolic restoration, and PD-1 immune checkpoint inhibition suppressed invasion, reduced metastasis, and prolonged survival in mouse models. Our findings define the LEMCE as a self-reinforcing invasive and immunosuppressive niche and highlight its potential as a targetable vulnerability in HNSCC.