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

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, we performed single-cell RNA sequencing 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 in the 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 tumor microenvironment remodeling associated with HPV status, suggesting that the reduced immunosuppression in HPV-positive tumors may underlie their more favorable prognosis.