2. Academic Validation
  3. Artemisinin sensitizes triple negative breast cancer to immune checkpoint therapy through suppressing KEAP1-mediated PD-L1 degradation

Artemisinin sensitizes triple negative breast cancer to immune checkpoint therapy through suppressing KEAP1-mediated PD-L1 degradation

  • Biochem Pharmacol. 2026 Mar:245:117682. doi: 10.1016/j.bcp.2026.117682.
Zehua He 1,  Zhaoshuai Chen 2,  Lei Wang 3,  Ziyi Hu 3,  Zhixin Wang 3,  Jiehang Zhou 3,  Yiran Zhu 3,  Zhaorui Lyu 3,  Wencan Zhang 3,  Fan Lin 4,  Xu Cao 5,  Liqiong Xue 6
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center for Drug Target Identification and Delivery, and the Engineering Research Center of Cell and Therapeutic Antibody of the Ministry of Education, School of Pharmaceutical Sciences, State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, China; Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 2 Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University Nanjing, Jiangsu, China.
  • 3 Shanghai Frontiers Science Center for Drug Target Identification and Delivery, and the Engineering Research Center of Cell and Therapeutic Antibody of the Ministry of Education, School of Pharmaceutical Sciences, State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, China.
  • 4 Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University Nanjing, Jiangsu, China. Electronic address: [email protected].
  • 5 Shanghai Frontiers Science Center for Drug Target Identification and Delivery, and the Engineering Research Center of Cell and Therapeutic Antibody of the Ministry of Education, School of Pharmaceutical Sciences, State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, China. Electronic address: [email protected].
  • 6 Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China. Electronic address: [email protected].
PMID: 41506550 DOI: 10.1016/j.bcp.2026.117682
Abstract

Triple-negative breast Cancer (TNBC) remains a clinical challenge due to limited therapeutic options and frequent resistance to immunotherapy. While PD-L1 blockade shows promise, clinical responses are often inadequate. Here we demonstrated that augmenting PD-L1 expression on TNBC cells significantly enhances the efficacy of anti-PD-L1 therapy in murine models. Through a high-throughput screen of FDA-approved compounds, artemether (ART) emerged as a robust inducer of PD-L1 surface expression in multiple murine and human TNBC cell lines. Mechanistically, ART disrupts the interaction between the E3 ubiquitin Ligase adaptor KEAP1 and PD-L1, preventing KEAP1-mediated PD-L1 degradation and enhancing its stability and membrane localization. Concurrently, ART-induced KEAP1 inhibition activates NRF2, leading to increased PD-L1 transcription. Critically, in syngeneic TNBC mouse models, ART synergistically enhanced the antitumor efficacy of atezolizumab, promoting tumor regression and increasing intratumoral CD8+ T cell infiltration and cytotoxicity. Our findings reveal a novel mechanism by which ART upregulates PD-L1 through KEAP1 inhibition and establish ART as a promising pharmacological agent to improve the clinical outcomes of PD-L1 checkpoint blockade immunotherapy in TNBC.

Keywords

Artemether; KEAP1; PD-L1 blockade; Triple-negative breast cancer.

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