Imbalance Between CD44 and STAT3 Enhances Spheroid Viability and Impairs Pembrolizumab Response in Urothelial Cancer

Background/Aim: Cancer cell plasticity is tightly linked to therapeutic resistance in urothelial carcinoma (UC). Signal transducer and activator of transcription 3 (STAT3) and CD44 play crucial roles in plasticity, but their potential crosstalk in the therapeutic context has not yet been fully elucidated. This study aimed to unveil the shared and distinct roles of STAT3 and CD44 and obtain a better understanding of targeted therapy in UC.

Materials and Methods: T24 bladder cancer cells were genetically ablated for STAT3 and CD44 and their plasticity was subsequently assessed. Phosphorylated-STAT3 (pSTAT3) and CD44 expression was determined using tissue microarrays in 16 patients who received pembrolizumab therapy for UC, and the association of their expression levels with patient prognosis was investigated.

Results: Ablation of STAT3 or CD44 expression resulted in the dysregulation of vimentin expression and promotion of cell spheroid viability. Patients with imbalanced pSTAT3 and CD44 expression had significantly shorter progression-free survival and overall survival.

Conclusion: Functional imbalance of STAT3 and CD44 may promote cancer cell plasticity and result in impaired pembrolizumab response in patients with advanced UC.