Inhibiting NEDD4 in triple-negative breast cancer cells reprograms tumor immune microenvironment via the β-TrCP/YAP/ECM axis.

ABSTRACT: Tumor immune microenvironment greatly influences triple-negative breast cancer (TNBC) progression. Identifying targets to convert "cold" tumors into "hot" tumors holds promise for improving treatment outcomes. Here, we show that high expression of NEDD4, an HECT-type E3 ubiquitin ligase, correlates with poor prognosis and reduced CD8⁺ T cell infiltration in TNBC patients. NEDD4 depletion in TNBC cells significantly inhibits tumor growth through enhancing CD8⁺ T cell-mediated cytotoxicity in immunocompetent hosts. Mechanistically, NEDD4 depletion stabilizes β-TrCP, leading to YAP ubiquitination and degradation. Downregulated YAP reprograms the immunosuppressive tumor extracellular matrix (ECM) to increase CD8⁺ T cell infiltration. Furthermore, a small-molecu

SUBMITTER: Su N 

PROVIDER: S-EPMC12629805 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature