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

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-molecule inhibitor of NEDD4, XMU-MP-10, exhibits significant in vivo efficacy in inhibiting TNBC tumor growth by enhancing CD8 + T cell infiltration in mouse models. Collectively, our findings suggest that the genetic depletion or pharmacological inhibition of NEDD4 enhances antitumor immune responses via the β-TrCP/YAP/ECM cascades, offering a promising therapeutic strategy for TNBC treatment. • High NEDD4 level correlates with poor TNBC prognosis and reduced CD8 + T cell infiltration • NEDD4 depletion inhibits tumor growth by increasing intratumoral CD8 + T cell infiltration • NEDD4 depletion triggers β-TrCP-mediated YAP degradation to reprogram tumor ECM • The NEDD4 inhibitor XMU-MP-10 exerts potent anti-tumor effects against TNBC in vivo Su et al. reveal that NEDD4 depletion in TNBC reprograms the immunosuppressive tumor microenvironment via the β-TrCP/YAP/ECM axis, thereby enhancing antitumor immune responses. Furthermore, they identify XMU-MP-10, a NEDD4 inhibitor, capable of suppressing TNBC tumor growth in both syngeneic and humanized immune system mouse models.