Spatially resolved multiomics reveals the self-enforcing property of the leading-edge multicellular ecosystem of head and neck cancer
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (13)
Zhi-Fei Su
State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu
Chen-Zhou Wu
State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu
Hao-Ran Ding
State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu
Qi Zhan
State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu
Yong-Bing Ba
Shanghai OE Biotech. Co. Ltd.
Lei Cheng
Ji-Yao Li
State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu
Xue-Dong Zhou
State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu
Long-Jiang Li
State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu
Li-Xin Zhang
State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology
Jing Li
Yi Li
Biao Ren
State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu