Breaking down barriers—hemidesmosomal dysfunction and epithelial dysregulation in squamous cell carcinoma progression

This critical review examines whether and how disruption of epithelial barrier function—with a particular focus on hemidesmosomal remodelling, polarity regulators and basement membrane integrity—contributes to the initiation and progression of squamous cell carcinoma (SCC). We synthesise multidisciplinary evidence from molecular studies, immunohistochemistry, spatial profiling and experimental models, and highlight stage-specific patterns of adhesion and polarity change from normal epithelium through dysplasia to invasive disease. The assembled data indicate that selective remodelling of cell–matrix and cell–cell adhesion can reprogramme intracellular signalling, promote epithelial plasticity (including partial EMT), and facilitate collective modes of invasion while reshaping stromal and immune microenvironments. Empirical findings discussed include stage-associated changes in hemidesmosomal protein expression and architectural features that track with malignant risk, as well as mechanistic studies linking hemidesmosome disassembly to focal adhesion signalling. We conclude that disrupted epithelial organisation can act as a disease-modifying factor in SCC and that further mechanistic, spatial and longitudinal studies are needed to establish causality and to assess whether restoration of barrier integrity or targeting of resulting vulnerabilities has therapeutic or prognostic value.