Clinical integration of tertiary lymphoid structures and B cells in non-muscle-invasive and muscle-invasive bladder cancer

This is the authors' abstract. We don't add key points for this paper.

Objective Bladder cancer is immunogenic, but immune readouts are often oversimplified when reduced to total cell counts. For B cells and tertiary lymphoid structures (TLS), collectively referred to as B/TLS, spatial organization and functional maturity appear more informative. This review outlines how these features may add to established biomarkers in non-muscle-invasive and muscle-invasive disease. Methods A targeted review of PubMed literature covering the period up to September 2025 was performed to synthesize current evidence on B-cell biology, TLS architecture and maturation, spatial immune organization, Bacillus Calmette–Guérin therapy, and immune checkpoint blockade in bladder cancer. Results Mature TLS are typically characterized by germinal centers and follicular dendritic-cell networks and may also contain high endothelial venules. They mark an immune-inflamed tumor state that is repeatedly associated with longer survival and increased likelihood of benefit from programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade. In muscle-invasive bladder cancer, C-X-C motif chemokine ligand 13-driven lymphoid programs and TLS-enriched classes align with a favorable prognosis and higher immunotherapy response rates. In non-muscle-invasive bladder cancer, B-cell signals are more heterogeneous. Mature, organized TLS generally are associated with lower recurrence risk, whereas diffuse or regulatory-leaning B-cell infiltrates within PD-L1-rich and myeloid-rich environments may indicate adverse outcomes. Early studies suggest that practical TLS scoring on transurethral resection of bladder tumor, with maturity and location explicitly noted, is feasible. Across both non-muscle-invasive bladder cancer and muscle-invasive bladder cancer, trial and translational data point toward a role for B/TLS profiles as supportive signals, especially when interpreted with PD-L1, tumor mutational burden, and circulating tumor DNA. Conclusion B/TLS readouts are moving beyond descriptive pathology. Standardized maturity-aware scoring and harmonized sampling may help integrate them into pathology reports, while prospective validation is required to define cutoffs, test on-treatment dynamics, and establish their place in clinical decision-making.