The role of the tumor microenvironment in penile carcinoma and emerging therapeutic concepts: A review

• Penile carcinoma (PC) exhibits heterogenous clinical courses with poor prognosis in advanced and metastasized tumor stages. • Deciphering the tumor microenvironment in PC is fundamental to understand prognostic differences among histologic subtypes and predicting responses to immune-checkpoint-inhibitors. • Several phase II clinical trials are currently investigating PD-1 and PD-L1 inhibitors, either as monotherapy or in combination with platinum-based chemotherapy and EGFR inhibitors. • Clinical phase II trials are investigating the antibody-drug-conjugates (ADCs) sacituzumab govitecan and enfortumab vedotine are raising further hope for prolonged survival in advanced/metastasized tumor stages. Penile carcinoma (PC) is a rare malignancy with substantial geographic and etiological heterogeneity. Histologically, it is stratified into HPV-associated and HPV-independent subtypes, each with distinct clinical behaviors and molecular features. Prognostic markers such as histologic tumor stage, grade, nodal involvement, and lymphovascular invasion guide therapeutic decision-making, while emerging predictive biomarkers—HPV status, PD-L1 expression, and tumor mutational burden—show potential to personalize systemic treatment. Advances in tumor microenvironment (TME) profiling have revealed immune and stromal signatures that have the potential to influence treatment response. While immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) show early clinical benefits, biomarker-driven patient selection remains essential to optimize efficacy. This review summarizes current evidence on the TME in PC and novel therapeutic strategies, aiming to guide future personalized treatment strategies.