Single-cell and spatial transcriptomics define the LAMC2+ malignant subtype orchestrating vasculogenic mimicry-mediated resistance in head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy with limited therapeutic options. Here we combine single-cell RNA sequencing, spatial transcriptomics, clinical cohorts, and experimental models to dissect malignant epithelial heterogeneity and its impact on disease progression and treatment response. We identify a malignant subtype characterized by partial epithelial–mesenchymal transition (pEMT), enriched at the invasive front and associated with poor prognosis. This pEMT subtype exhibits pronounced vasculogenic mimicry (VM) potential and resistance to anlotinib-based neoadjuvant therapy, driven by high expression of the extracellular matrix component LAMC2. Functional assays demonstrate that LAMC2 promotes proliferation, VM formation, and resistance to anti-angiogenic therapy. Mechanistically, TGF-β signaling enhances LAMC2-driven VM, while blockade of TGF-β synergizes with anlotinib to suppress tumor growth. In addition, LAMC2–CD44 interactions shape an immunosuppressive tumor microenvironment enriched in M2 macrophages, cancer-associated fibroblasts, and regulatory T cells. Together, these findings define a LAMC2 + pEMT subtype that mediates therapeutic resistance through the TGF-β–pEMT/LAMC2–VM axis, highlighting a potential strategy to overcome resistance and reprogram the HNSCC microenvironment.