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
  • 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: [email protected].
  • 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: [email protected].
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.
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