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

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.