Pseudomonas aeruginosa exacerbates bladder cancer progression by activating cancer-driven immunosuppression

Abstract Pseudomonas aeruginosa infection is still a serious problem among immunocompromised patients who have advanced urinary tract malignancies, yet the impact of P. aeruginosa on disease progression remains poorly defined. Here, we show that urinary tract infections (UTI) caused by P. aeruginosa exacerbated bladder cancer progression in murine models, primarily by inducing an immunosuppressive tumor microenvironment. Mechanistically, P. aeruginosa activated Toll-like Receptor 5 (TLR5) on bladder cancer cells, triggering phosphorylation of ERK1/2 and subsequent secretion of the chemokine CCL20. This signaling axis promoted the recruitment of myeloid-derived suppressor cells (MDSCs), thereby reinforcing immunosuppression within the tumor microenvironment and exacerbating bladder cancer growth. In clinical samples, 16S rRNA sequencing and transcriptome analysis of bladder cancer tissues confirmed the presence of P. aeruginosa, with its abundance significantly correlating with advanced disease stages and elevated CCL20 expression. Collectively, these data identify a role for P. aeruginosa in promoting bladder cancer progression through TLR5-ERK1/2-CCL20–mediated MDSC recruitment, shedding light on the intricate interplay between microbial infection and cancer pathogenesis. These insights highlight potential therapeutic targets to disrupt infection-driven cancer progression.