Tertiary Lymphoid Structures in Genitourinary Cancers: A Comprehensive Review

Alvaro Abreu¹Alejandra Viera Plasencia¹Mercy Iribarren¹Carter Wegner¹Joana Nuraj¹Elai Davicioni²Hisham F. Bahmad^3,4*Mohammed Shahait^5*

• ¹Florida International University Herbert Wertheim College of Medicine, Miami, United States
• ²Veracyte, Inc, South San Francisco, CA 94080, USA, South San Francisco, United States
• ³Department of Pathology and Laboratory Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, Beirut, United States
• ⁴University of Miami Miller School of Medicine, Miami, United States
• ⁵Department of Urology, University of California at Irvine, 19200 Jamboree Road Suite 5100, Irvine, CA, United States, Irvine, United States

Tertiary lymphoid structures (TLSs) are lymphoid cell clusters that form in non-lymphoid tissues in response to chronic inflammation and function as sites for localized, antigen-specific immune responses, potentially enhancing anti-tumor immunity. This review examines TLS presence, composition, and clinical significance across genitourinary (GU) cancers to evaluate their potential as prognostic and therapeutic targets. In prostate cancer, TLSs are infrequently found due to a typically immunologically inactive tumor microenvironment (TME), but when present, they correlate with improved outcomes and reduced recurrence, especially when structurally mature with active germinal centers (GCs). Bladder cancer, in contrast, demonstrates increased TLS activity, particularly in high-grade disease, with high TLS density associated with superior responses to Bacillus Calmette-Guérin (BCG) therapy and anti-PD-L1 treatment. In testicular seminomas, TLSs have been associated with a more favorable prognosis, whereas non-seminomatous germ cell tumors demonstrate TLS suppression driven by SERPINB9-mediated downregulation of chemokines that promote their development. In clear cell renal cell carcinoma (ccRCC), TLSs correlate with improved survival and enhanced immunotherapy responses, although elevated CXCL13 expression may paradoxically signal more aggressive disease. Unlike ccRCC, TLSs are infrequent in papillary and chromophobe RCC, reflecting a less-inflamed TME that likely contributes to reduced immunotherapy responsiveness and prognostic value. TLSs in penile squamous cell carcinomas show enhanced immune infiltration and improved overall survival (OS) independent of stage. Notably, mature TLSs are key for effective anti-tumor immunity, whereas immature TLSs may fail to generate an adequate response. Collectively, these findings highlight TLSs as prognostic biomarkers with prognostic value and therapeutic potential in GU malignancies.