Background: Cutaneous squamous cell carcinoma (cSCC) is a metastatic-prone malignancy where risk stratification guides management. However, current stratification lacks robust biological underpinnings, limiting its ability to predict progression and tailor therapies. The molecular drivers of TME evolution across risk strata remain elusive, hindering personalized approaches. Methods: Single-cell sequencing and clinical risk profiling were integrated to to dissect tumour microenvironment (TME) dynamics underlying cSCC progression across risk strata. Results: The very highrisk group exhibited a skewed neutrophil-to-lymphocyte ratio and progressive depletion of γδT cells, a subset linked to anti-tumour surveillance. Concurrently, cancer-associated fibroblasts (CAFs) displayed risk-dependent enrichment, with inflammatory CAFs (iCAFs) predominating in advanced stages, suggesting their role in fostering immune suppression and metastasis. Further, dysregulation of CXCL8 (pro-inflammatory chemokine), TGFβ(matrix remodelling), and IGFBP7 (stromal crosstalk) emerged as hallmark transcriptional features of very highrisk tumours, correlating with epithelial-mesenchymal transition. Conclusions: This study establishes iCAFs and γδT cell loss as central drivers of cSCC aggressiveness and nominates CXCL8/TGFβ/IGFBP7 dysregulation as a biomarker framework for risk stratification. Collectively, these findings unveil actionable therapeutic targets and provide a molecular basis for personalizing management strategies, particularly for identifying and treating very highrisk cSCC patients who may benefit from intensified surgical approaches, adjuvant therapies, or novel targeted interventions.
Xia et al. (Tue,) studied this question.
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