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Bladder and Urothelial Cancer Treatments / Immune Cells in Cancer · Journal article
Frontiers in Immunology · September 8, 2026
Raises a question worth testing. It does not answer one.
This narrative review synthesizes evidence and hypotheses regarding tertiary lymphoid structures (TLS) as potential spatial biomarkers of local adaptive immunity in urothelial carcinoma, particularly in the post-BCG setting. The authors emphasize that TLS maturation status and spatial localization may capture tumor immune microenvironment heterogeneity poorly predicted by TMB and PD-L1 alone, but explicitly state that relationships with BCG failure and response to checkpoint inhibitors or enfortumab vedotin remain largely correlative and require prospective validation. The review does not provide new empirical data and cautions against current clinical use of TLS as a stand-alone biomarker.
Journal article. Patients with high-risk non-muscle-invasive bladder cancer and urothelial carcinoma, particularly in the post-BCG era..
TLS appear to exist across a maturation continuum from early, disorganized lymphoid aggregates to mature, germinal center-containing follicles in UC. Existing biomarkers such as tumor mutational burden and PD-L1 expression show limited and inconsistent predictive performance in UC. TLS localization within lamina propria, tumor stroma, or invasive front may be associated with distinct immune contexts and clinical outcomes.
Safety was not reported in the material analysed. Check the source before drawing any conclusion about harm.
Clinicians should not currently use TLS status as a stand-alone biomarker for treatment selection in urothelial carcinoma. The review identifies TLS as a promising research direction requiring prospective validation before clinical adoption, and suggests potential future applications in bladder-preservation studies and as an adjunctive biomarker.
A narrative review synthesizing current evidence and raising mechanistic questions about tertiary lymphoid structures in urothelial carcinoma, without new empirical data or prospective validation of proposed biomarker relationships.
Clinicians should not currently use TLS status as a stand-alone biomarker for treatment selection in urothelial carcinoma. The review identifies TLS as a promising research direction requiring prospective validation before clinical adoption, and suggests potential future applications in bladder-preservation studies and as an adjunctive biomarker.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
What is missing. This record has no reported figures. That is a gap in the analysis, not a judgement about the study.
Urothelial carcinoma (UC) remains a persistent clinical challenge in the post-Bacillus Calmette-Guérin (BCG) era, particularly because a substantial proportion of patients with high-risk non-muscle-invasive bladder cancer (NMIBC) experience recurrence or progression despite standard intravesical immunotherapy. Although immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) have expanded the therapeutic armamentarium, widely studied biomarkers such as tumor mutational burden (TMB) and PD-L1 expression show limited and inconsistent predictive performance in UC, which may partly reflect their inability to capture the spatial organization and functional states of the tumor immune microenvironment (TIME). Tertiary lymphoid structures (TLS), ectopic lymphoid aggregates that develop in non-lymphoid tissues at sites of chronic inflammation or cancer, have emerged as candidate mediators and spatial markers of local adaptive immunity. In UC, TLS appear to exhibit spatial heterogeneity and may exist across a maturation continuum from early, disorganized lymphoid aggregates to mature, germinal center-containing follicles; their localization within the lamina propria, tumor stroma, or invasive front may be associated with distinct immune contexts and clinical outcomes. This review provides a urology-centric perspective on TLS biology in UC, emphasizing how the anatomical and immunological niche of the bladder, including urinary exposure, the urinary microbiome, BCG-associated inflammation, and stromal remodeling, may shape the conditions under which TLS develop and function. We critically discuss TLS maturation status as a potential spatial biomarker, while emphasizing that its relationship with BCG failure and subsequent response to PD-1/PD-L1 blockade or enfortumab vedotin (EV)-based therapy remains largely correlative and requires prospective validation. Furthermore, we explore emerging strategies that may modulate TLS-associated immune architecture, including STING agonist instillation and LTβR pathway modulation, and discuss how TLS could be tested as an adjunctive biomarker in future bladder-preservation studies for high-risk T1 disease. By synthesizing current evidence and methodological advances in spatial transcriptomics, we underscore the translational imperative of viewing UC as a malignancy with heterogeneous local immune architecture, including candidate tertiary lymphoid structures. At present, TLS should not be used as a stand-alone biomarker for selecting bladder preservation, radical cystectomy, intravesical therapy continuation, or systemic treatment switching.
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