Bladder cancer is a prevalent but currently understudied cancer type and patient outcomes are poor when it progresses to the muscle-invasive stage. Current research in bladder cancer focuses on the genetic and epigenetic alterations occurring within the urothelial cell compartment; however, the stromal compartment receives less attention. Dynamic changes and intercellular communications occur in the tumour microenvironment (TME) of the bladder - a new concept and niche that we designate as the bladder TME (bTME) - during tumour evolution, metastatic progression and in the context of therapeutic response. Collagens and their cognate receptors, the discoidin domain receptors, have a role in various steps of the metastatic cascade and in immune checkpoint resistance. Furthermore, the presence of another TME niche, the metastatic TME (met-TME), is a novel concept that could support divergent progression of metastatic colonization in different organs, resulting in distant metastases with distinct characteristics and genetics from the primary tumour. The stroma has divergent roles in mediating therapeutic response to BCG immunotherapy and immune checkpoint inhibitors, as well as conventional chemotherapy or trimodality therapy (that is, maximal transurethral resection of bladder tumour, chemotherapy and radiotherapy). The local bTME and distant met-TME are currently conceptually and therapeutically unexploited niches that should be actively investigated. New biological insights from these TMEs will enable rational design of strategies that co-target the tumour and stroma, which are expected to improve the outcomes of patients with advanced bladder cancer.
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