The Immune Microenvironment in Penile Squamous Cell Carcinoma: Distinctions Between HPV-Driven and HPV-Independent Pathways

Background: Penile squamous cell carcinoma (pSCC) is a global health burden with poor systemic treatment efficacy for advanced disease, relying on pathway-agnostic regimens despite two distinct carcinogenic pathways (HPV-driven vs. HPV-independent). We conducted an integrative review to systematically compare the tumor immune microenvironment (TIME) of HPV-driven and HPV-independent pSCC to guide immunotherapy stratification. Methods: An integrative review of 21 studies, including single-cell/spatial transcriptomics and a Phase II clinical trial, synthesized evidence from over 4,500 pSCC patients published between January 2020 and April 2026. Results: HPV-positive pSCC presents an immunologically active but partially suppressed TIME, defined by significantly higher CD8+ T-cell infiltration and lower immune checkpoint co-expression and exhaustion (e.g., TIGIT). HPV-negative tumors exhibit a broadly immunosuppressive niche marked by elevated PD-L1 prevalence (51.4% pooled), increased regulatory T-cell and M2-macrophage polarization, and multi-checkpoint co-exhaustion (PD-1, TIM-3, LAG-3). PD-L1 overexpression is associated with shorter cancer-specific survival. Clinically, HPV positivity and CD8+ T-cell density independently predicted progression-free survival benefit from atezolizumab. Conclusion: These findings establish HPV status and TIME composition as actionable determinants of immunotherapy benefit. We recommend prospective integration of HPV testing and tumor-infiltrating lymphocyte quantification into future randomized trials to guide patient selection and explore combinatorial checkpoint blockade, particularly for the multi-exhausted HPV-negative disease subset.