Decoding the Cellular Heterogeneity and Malignant Progression of Human Penile Squamous Cell Carcinoma by Single‐Cell RNA Sequencing

Penile squamous cell carcinoma (PSCC) is a rare genitourinary malignancy, and factors of its tumor microenvironment (TME) could serve as prognostic indicators for tumor recurrence and metastasis. Here, we generated a comprehensive single-cell map of PSCC (66 421 cells) and identified 9 distinct cell populations with samples from nine tumor samples and six adjacent normal samples. Among the malignant cells, SEMA3C^high Mals was found to be associated with epithelial-mesenchymal transition. T cells in tumor tissues are in a highly exhausted state, while SPP1^high TAMs were observed to promote tumor progression. Cancer-associated fibroblasts were found to interact with malignant cells to facilitate EMT through several pathways. Notably, there is a specific type of pericyte called POSTN⁺ pericytes, which can promote angiogenesis and extracellular matrix remodeling in PSCC. Finally, SEMA3C was identified as an effective biomarker reflecting cancer stage and microvessel density. Overall, we investigated the heterogeneity of TME from a single-cell perspective and demonstrated that SEMA3C serve as an effective biomarker for predicting lymph node metastasis and prognosis in PSCC. These findings may offer valuable insights for future therapeutic strategies.