Single-cell transcriptomic profiling reveals distinct tumor microenvironments in HPV-associated penile squamous cell carcinoma

Abstract Background Penile squamous cell carcinoma (PSCC) is a rare yet potentially lethal malignancy, often resulting in devastating disfigurement, with a 5-year survival rate of only ∼50%. Human papillomavirus (HPV) infection is implicated in approximately half of PSCC cases and is associated with improved clinical outcomes; however, the underlying mechanisms remain poorly understood. Methods To elucidate HPV-associated differences in the tumor microenvironment (TME), we performed single-cell RNA sequencing (scRNA-seq) on tumors from 11 treatment-naïve PSCC patients, analyzing a total of 52 980 single cells. Unsupervised clustering identified 49 distinct cellular clusters across immune and stromal compartments. Results HPV-positive tumors exhibited an increased abundance of mast cells and a reduction of proliferative macrophages subpopulation compared to HPV-negative tumors. Notably, CD8+ T cells in HPV-positive PSCC expressed lower levels of immune checkpoint molecules, suggesting a less exhausted immune state. Conversely, TIGIT and its ligands were significantly enriched in HPV-negative tumors, potentially fostering an immunosuppressive niche. Conclusion Collectively, our study delineates the single-cell landscape of PSCC and highlights distinct TME remodeling associated with HPV status, suggesting that the reduced immunosuppression in HPV-positive tumors may underlie their more favorable prognosis.