ABSTRACT Objective Tissue inhibitor of metalloproteinase‐1 (TIMP1) is a secreted glycoprotein that controls matrix metalloproteinase activity and exerts pleiotropic signaling functions. We investigated the clinical relevance of TIMP1 in head and neck squamous cell carcinoma (HNSCC; TCGA‐HNSC), focusing on survival, immunologic contexture, pathway programs, and whether TIMP1‐associated transcriptional signals preferentially align with tumor‐intrinsic proliferative states or stromal/immune‐associated programs. Methods RNA‐seq and clinical data for TCGA‐HNSC were retrieved via UCSC Xena. TIMP1 expression was compared between tumor and normal tissues and across clinicopathologic strata. Overall survival (OS) and disease‐free survival (DFS) were analyzed using Kaplan–Meier models (median split). TIMP1‐centered transcriptome associations were characterized using correlation‐ranked enrichment analyses (Reactome/GO). In addition, phenotype‐based gene set enrichment analysis (GSEA) comparing TIMP1‐high versus TIMP1‐low tumors was performed using MSigDB Hallmark gene sets. Immune infiltration and checkpoint associations were evaluated with TIMER2.0. Subgroup analyses were conducted by TCGA HPV status. Results TIMP1 was upregulated in tumors versus normal tissues and tended to be higher in advanced grade/stage and HPV‐negative disease. High TIMP1 was associated with worse OS (HR≈1.3) and a trend toward shorter DFS. Correlation‐based enrichment highlighted extracellular‐matrix organization, collagen metabolism, glycosaminoglycan pathways, complement/platelet‐related programs, and downregulation of keratinization/differentiation processes. Phenotype‐based Hallmark GSEA further showed that TIMP1‐high tumors were strongly enriched for epithelial–mesenchymal transition and stromal/vascular and inflammatory programs (including angiogenesis, coagulation, inflammatory response, and complement signaling), whereas TIMP1‐low tumors were relatively enriched for cell‐cycle/proliferation programs (including G2M checkpoint, E2F targets, and mitotic spindle). Consistently, TIMP1 positively correlated with CD4+ T‐cell and macrophage signatures, NK‐cell markers (NCAM1), CAF markers (ACTA2, FAP, and PDGFRB), and immune checkpoints (PD‐L1, CTLA4, and TIGIT/LAG3), particularly in HPV‐negative tumors. Conclusions TIMP1 expression captures stromal remodeling and an immune‐interacting, checkpoint‐enriched microenvironment in HNSCC, associates with poor survival, and is most strongly linked to HPV‐negative biology. Integrating correlation‐based enrichment with TIMP1‐high/low phenotype‐based GSEA supports a TIMP1‐high state characterized by EMT/vascular–inflammatory programs, contrasting with a more proliferation‐dominant program in TIMP1‐low tumors. These findings nominate TIMP1‐centered ECM/immune circuits as candidate biomarkers and potential co‐targetable nodes in HNSCC.
Kurosaka et al. (2026) studied this question.