The predictive role of tertiary lymphoid structures in the prognosis and response to immunotherapy of bladder cancer patients: a systematic review and meta-analysis.

BACKGROUND

The association between tertiary lymphoid structures (TLS) and clinical outcomes in bladder cancer (BCa) patients, particularly their value in predicting immunotherapy response, remains inconsistent and has not been systematically evaluated.

OBJECTIVE

This systematic review and meta-analysis aimed to: (1) evaluate the association between TLS and survival outcomes in BCa; (2) examine the relationship between TLS and clinicopathological characteristics; and (3) summarize evidence on TLS and immunotherapy response.

METHODS

We systematically searched PubMed, Embase, and Web of Science from inception to February 1, 2026. Hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) were extracted and pooled. The study protocol was registered with PROSPERO (CRD420261282595).

RESULTS

Eight studies involving 1706 patients were included in the quantitative synthesis. Pooled analysis revealed that high TLS levels were significantly associated with improved OS (HR = 0.49, 95% CI: 0.33-0.74), PFS (HR = 0.51, 95% CI: 0.45-0.58), and DFS (HR = 0.42, 95% CI: 0.22-0.79). TLS showed a significant correlation only with tumor multiplicity among various clinicopathological features. Qualitative synthesis of six studies suggested that while baseline TLS had limited predictive value for immunotherapy response, therapy-induced increases in TLS number, density, and maturation were consistently associated with favorable treatment outcomes.

CONCLUSION

High TLS levels are associated with favorable survival outcomes in bladder cancer patients, supporting their role as a prognostic biomarker. Therapy-induced TLS dynamics, rather than baseline status alone, may be a more relevant predictive biomarker for immunotherapy efficacy. These findings warrant validation in larger, prospective studies.