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

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

  • Cell Rep Med. 2025 Oct 21;6(10):102420. doi: 10.1016/j.xcrm.2025.102420.
Nan Su 1,  Wenhua Lian 1,  Baoding Zhang 1,  Yuan Tian 1,  Linying Li 1,  Yiyu Chen 1,  Xiang Zhi 1,  Taoling Zeng 2,  Qiao Wu 2,  Lanfen Chen 2,  Dawang Zhou 2,  Hong-Rui Wang 2,  Shih-Chin Cheng 2,  Li Li 3,  Xianming Deng 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian 361102, China; Cancer Research Center of Xiamen University, Xiamen 361102, China.
  • 2 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; Cancer Research Center of Xiamen University, Xiamen 361102, China.
  • 3 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian 361102, China; Cancer Research Center of Xiamen University, Xiamen 361102, China. Electronic address: lli@xmu.edu.cn.
  • 4 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian 361102, China; Cancer Research Center of Xiamen University, Xiamen 361102, China; Department of Hematology, the First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen 361003, China. Electronic address: xmdeng@xmu.edu.cn.
PMID: 41125065 DOI: 10.1016/j.xcrm.2025.102420
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-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.

Keywords

E3 ubiquitin ligase; antitumor immunity; triple-negative breast cancer; tumor microenvironment.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z