Metastatic urothelial cell carcinoma (UCC) is a significant public health burden with a median survival estimated at about 15 months. The use of immunotherapy with immune checkpoint inhibitors has greatly improved outcomes but only benefits a minority (~20%) of patients. In this review we discuss the evidence showing how a key molecular pathway known as Wnt/β-catenin signaling can be a driver of immunotherapy resistance and how these insights can serve as lessons for improving future treatment of urothelial carcinoma.

Urothelial cell carcinoma (UCC) is a significant public health burden. It accounts for approximately 90 percent of all bladder cancers with an estimated 200,000 annual deaths globally. Platinum based cytotoxic chemotherapy combinations are the current standard of care in the frontline setting for metastatic UCC. Even with these treatments the median overall survival is estimated to be about 15 months. Recently, immune checkpoint inhibitors (ICIs) have demonstrated superior clinical benefits compared to second line chemotherapy in UCC treatment. However only a minority of patients (~20%) respond to ICIs, which highlights the need to better understand the mechanisms behind resistance. In this review, we (i) examine the pathophysiology of Wnt/β-catenin signaling, (ii) discuss pre-clinical evidence that supports the combination of Wnt/β-catenin inhibitors and ICI, and (iii) propose future combination treatments that could be investigated through clinical trials.