Tumor-derived microRNAs as early predictive biomarkers for toxicity induced by immunotherapy in urothelial cancer

Immune checkpoint inhibitors (ICIs) have revolutionized advanced urothelial carcinoma (UC) treatment, yet efficacy is limited by immune-related adverse events (irAEs) necessitating treatment termination. Identifying biomarkers to predict irAE susceptibility is a critical unmet need for patient management. This exploratory study sought to identify tumor microRNA (miRNA) expression signatures associated with irAE risk in UC patients treated with ICIs. We analyzed a retrospective cohort of 108 UC patients treated with ICI therapy (PD-1 and PD-L1 blockade). Baseline tumor miRNA expression was quantified via RT-qPCR. Statistical analysis was performed to identify associations between baseline miRNA expression levels and the subsequent development of specific irAEs. The irAE prevalence was high, affecting approximately one-third of the cohort. Low baseline tumor expression of miR-34c-5p and miR-493-5p was significantly associated with an increased risk of developing pneumonitis ( p = 0.037) and asthenia ( p = 0.027). Furthermore, borderline associations were observed for miR-146a-5p (hepatitis), miR-222-3p (pneumonitis) and miR-641 (anemia), supporting their roles in regulating immune homeostasis. In this exploratory study, tumor miRNA expression profiles, particularly the low baseline expression of miR-34c-5p and miR-493-5p, suggest a possible relationship with higher risk of developing toxicity during ICI treatments. Although further studies are needed to validate the utility of tumor miRNAs expression as biomarkers of ICI-induced toxicity, these preliminary results remark their possible utility as biomarkers in the clinical management of adverse effects from ICI treatment in UC patients.