Penile cancer is a rare but aggressive malignancy, characterized by early lymphatic spread which is the most critical prognostic factor. Treatment options for patients with locally advanced and metastatic disease are limited, primarily relying on cisplatin-based chemotherapy, which is characterized by high toxicity and early resistance. In recent years, there has been a growing interest on translational research exploring the tumor microenvironment, enabling the identification of novel potential therapeutic targets. Emerging preclinical evidence supports the use of immune checkpoint inhibitors, antibody–drug conjugates and novel exploratory therapies targeting myeloid-derived suppressor cells and tumor associated macrophages, as well as their combinations. However, robust phase III trials investigating such therapies are currently lacking. A deeper understanding of the penile cancer immune landscape and the role of specific mutations in carcinogenesis, might lead to the development of novel combination strategies to overcome cisplatin resistance and disease progression, and to a better selection of patients for inclusion in future clinical trials.
