MiR-145 reprogramming facilitates fibrotic trajectory in the tumor microenvironment

The fibrotic subtype of the tumor microenvironment characterized by epithelial-mesenchymal transition, fibrosis, angiogenesis and immune exclusion, predicts poor outcomes across diverse malignancies, yet the role of miR-145 in this context remains unexplored. Leveraging The Cancer Genome Atlas head and neck squamous cell carcinoma (HNSCC) and breast cancer (BRCA) databases, we demonstrate that miR-145 reprogramming recapitulates a noninflamed fibrotic phenotype with immune exclusion. In high miR-145 tumors, EMT programs persist alongside abundant cancer-associated fibroblasts, matrix remodeling and angiogenesis, with upregulation of NOTCH, TGF-β, myogenesis, hypoxia, Hedgehog, and Wnt/β-catenin signaling and downregulation of interferon-γ and JAK-STAT pathways. Our findings illustrate that cancer-stromal juxtacrine interactions activate NOTCH signaling, forming a positive feedback loop that amplifies miR-145 expression and is reinforced by miR-145 promoter hypomethylation. High miR-145 promotes autophagy and mitochondrial oxidative phosphorylation (OXPHOS) metabolism in cancer cells, with GAPDH serving as a central hub linking metabolism, noninflamed immune modulation, and poor clinical outcomes. In vivo, high miR-145 carcinoma cells co-engrafted with fibroblasts drive tumor growth through enhanced metabolism, angiogenesis and immune evasion. This study establishes miR-145 as a driver and biomarker of the fibrotic tumor microenvironment to better inform future cancer therapy strategies.