Immunotherapy in the Management of Penile Cancer—A Systematic Review

Background/Objectives: Penile squamous cell carcinoma (PSCC) is a rare and challenging malignancy with limited treatment options for advanced disease stages. Immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic strategy, leveraging the immune system’s ability to counteract tumor-induced immune evasion. This systematic review aims to synthesize current evidence on the efficacy of ICIs in PSCC, with a focus on their application in advanced and refractory settings. Methods: A comprehensive literature search was conducted across PubMed, Web of Science, Embase, and ClinicalTrials.gov to identify studies investigating ICIs in the treatment of PSCC. Studies were selected based on predefined inclusion and exclusion criteria, and data on treatment efficacy, biomarker relevance, and safety were extracted and analyzed. Results: Clinical trials and real-world data indicate that ICIs can provide durable responses in a subset of patients with advanced PSCC, particularly those with biomarkers such as PD-L1 expression and HPV positivity. Combination approaches, including ICIs with chemotherapy or radiotherapy, as well as neoadjuvant or adjuvant use, show potential for expanding treatment paradigms. However, due to the rarity of PSCC, robust evidence remains limited, necessitating further research and international collaboration. Conclusions: ICIs represent a promising therapeutic avenue for PSCC, with the potential to improve patient outcomes and quality of life. However, optimizing treatment strategies requires enhanced patient stratification, exploration of earlier incorporation of ICIs, and investigation of novel combination therapies. Centralized care and collaborative research efforts are essential to advancing the role of immunotherapy in PSCC management.