Regulatory T cells in the bladder cancer tumor microenvironment: mechanisms of immune suppression and therapeutic opportunities

Abstract

Bladder cancer is characterized by a highly dynamic tumor microenvironment (TME) that critically influences tumor progression, immune evasion, and therapeutic responsiveness. Among the immune populations in the TME, regulatory T cells (Tregs) play a central role in maintaining immune tolerance but also suppress effective antitumor immunity. Increasing evidence suggests that Tregs accumulate in bladder tumors and are associated with disease progression and reduced response to immunotherapies. The bladder cancer TME provides multiple signals that promote Treg recruitment, expansion, and functional stabilization, including chemokine-mediated trafficking, metabolic adaptation, and cytokine-driven differentiation. Interactions between Tregs and other microenvironmental components, such as cancer-associated fibroblasts, tumor-associated macrophages, endothelial cells, and extracellular matrix elements, further reinforce the immunosuppressive niche that facilitates tumor survival and therapy resistance. Recent advances in single-cell transcriptomics, spatial profiling, and multiomics analyses have revealed substantial heterogeneity among tumor-infiltrating Tregs, suggesting the existence of specialized subsets with distinct functional and metabolic properties in the bladder TME. These emerging insights highlight the importance of understanding Treg–TME crosstalk in shaping the immune landscape of bladder cancer. Targeting the mechanisms regulating Treg recruitment, stability, or suppressive function may represent a promising strategy to enhance the efficacy of immunotherapies including Bacillus Calmette–Guérin therapy. This review summarizes recent advances in Treg biology in bladder cancer and highlights potential therapeutic strategies to modulate Treg-mediated immunosuppression in the TME.