肿瘤微环境
免疫系统
内德4
癌症研究
泛素
细胞外基质
乳腺癌
泛素连接酶
癌症
渗透(HVAC)
生物
细胞
癌细胞
细胞生长
细胞外
细胞毒性
免疫疗法
医学
化学
体内
细胞培养
乳腺肿瘤
循环肿瘤细胞
抗体
下调和上调
免疫学
作者
Nan Su,Wenhua Lian,Baoding Zhang,Yuan Tian,Linying Li,Linying Li,Yiyu Chen,Xiang Zhi,Taoling Zeng,Qiao Wu,Lanfen Chen,Dawang Zhou,Hongrui Wang,Shih‐Chin Cheng,Li Li,Li Li,Xianming Deng
标识
DOI:10.1016/j.xcrm.2025.102420
摘要
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.
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