hsa-miR-145-3p defines a fibro-inflammatory bladder cancer subtype with distinct therapeutic vulnerabilities.

Bladder cancer (BCa) remains a challenging malignancy due to its capacity for immune evasion and therapy resistance. This study comprehensively investigates the tumor-suppressive microRNA hsa-miR-145-3p using multi-omics data from the TCGA-BLCA cohort. We found that hsa-miR-145-3p is significantly downregulated in BCa tissues, and its low expression independently predicts advanced tumor stage, lymph node metastasis, and poor overall survival. Functional analyses revealed that hsa-miR-145-3p loss reshapes the tumor immune microenvironment by reducing CD8⁺ T cells and dendritic cells while increasing immunosuppressive M2 macrophages, Tregs, and neutrophils, leading to elevated stromal scores and TIDE-based immunotherapy resistance. Mechanistically, it targets key genes (e.g., ANO9, RAD54B, SRSF6) and modulates pathways including spliceosome, cell cycle, and PD-1/PD-L1 signaling. Low expression also confers resistance to gemcitabine/cisplatin but enhances susceptibility to Dasatinib. We conclude that hsa-miR-145-3p is a central immunoregulator and a promising biomarker for prognosis and therapy selection in BCa.