Cancer-associated fibroblasts in bladder cancer: Immunosuppressive mechanisms and therapeutic targeting

Bladder cancer (BCa) still confounds treatment and one of the main reasons why is the nature of the immunosuppressive tumor microenvironment formed by cancer-associated fibroblasts (CAFs). The response rate to immune checkpoint inhibitors (ICIs) is still low in CAF-rich BCa, emphasizing the need to develop therapeutically for more therapies aimed directly at CAFs. In the past few years advances has been made with single cell analysis and spatial transcriptomics that reveals a degree of heterogeneity of CAFs and that the CAF subtypes are plastic and occupy distinct regions of the tumor where they govern immune cell behavior, treatment responses and resistant phenotypes. The continued development and use of these cutting edge techniques has really moved the field of tumor biology and precision treatment approaches forward. In this review, we explore our current understanding of the spatial organization of CAF populations in BCa and how they are co-opted to regulate T-cell exclusion and exhaustion, and remodel the stroma. We also integrate new evidence on cytokine signaling networks, matrix related changes, and CAF-driven mechanisms that may weaken the effectiveness of ICIs and chemotherapy. In addition, we outline current strategies that aim to target or reprogram CAFs and highlight promising combination approaches that may help overcome stromal barriers. By linking spatial biology with functional pathways and therapeutic implications, this review provides a clearer framework for understanding CAF mediated immunosuppression in BCa and identifies directions that may support the development of more effective treatments.