An MMP-14/STAT3 feedback loop upregulates PD-L1 to drive immunosuppression and tumorigenesis in bladder cancer

Bladder cancer is a common genitourinary malignancy in which immune checkpoint signaling contributes to treatment resistance. Matrix metalloproteinase MMP-14 degrades the extracellular matrix to facilitate cancer cell invasion, but its intracellular signaling functions remain incompletely characterized. Using TCGA data, all-human cell models, and T cell co-culture assays, we showed that MMP-14 expression correlated with clinicopathological features, negatively regulated immune processes, and was associated with regulatory T (Treg) cell enrichment. MMP-14 promoted proliferation and reduced apoptosis of bladder cancer cells and, in co-culture, suppressed T-cell-mediated killing. Mechanistically, MMP-14 was regulated by STAT3 and directly interacted with STAT3, promoting STAT3 phosphorylation at Y705 and upregulating PD-L1 expression. These results define an MMP-14/STAT3/PD-L1 axis that drives T cell dysfunction and Treg accumulation in bladder cancer, suggesting a target for overcoming immunotherapy resistance.