Zhifei Su, Chen-Zhou Wu, Haoran Ding, Qi Zhan, Yongbing Ba, Lei Cheng, Ji-Yao Li, Xuedong Zhou, Long-Jiang Li, Li-Xin Zhang, Jing Li, Yi Li, Biao Ren
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.