BET inhibitors (BETi) exhibit a strong anti-tumor activity in triple-negative breast cancer (TNBC). However, BETi resistance has been reported in TNBC. The mechanisms of resistance have not been demonstrated. Tumor-associated macrophages (TAMs) are frequently involved in cancer cells resistance to chemotherapy, also associated with poor prognosis in TNBC. However, the role of TAMs in BETi resistance remains unknown. Here, we found that BETi JQ1 and I-BET151 exerted anti-tumor effects in TNBC by decreasing IKBKE expression to attenuate NF-κB signaling. TAMs have been reported to associate with chemoresistance in breast cancer. Here, we firstly found that TNBC-stimulated TAMs activated NF-κB signaling by upregulating IKBKE expression to enhance breast cancer cells resistance to BETi. The IKBKE levels were also proved to be higher in clinical TNBC tissues than Non-TNBC tissues, suggesting feedback induction of IKBKE expression by TNBC-stimulated TAMs in TNBC. Moreover, the induction of IKBKE by TAMs in TNBC cells was identified to be associated with STAT3 signaling, which was activated by TAM-secreted IL-6 and IL-10. Lastly, the combination of inhibitors of BET and STAT3 exerted a synergistic inhibition effects in TAM-cocultured or TAM CM-treated TNBC cells in vitro and in vivo. Altogether, our findings illustrated TNBC-activated macrophages conferred TNBC cells resistance to BETi via IL-6 or IL-10/STAT3/IKBKE/NF-κB axis. Blockade of IKBKE or double inhibition of BET and STAT3 might be a novel strategy for treatment of TNBC.Keywords: BET inhibition; IKBKE; Macrophages; STAT3; Triple-negative breast cancer.

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乐备实（上海优宁维生物科技股份有限公司旗下全资子公司），是国内专注于提供高质量蛋白检测以及组学分析服务的实验服务专家，自2018年成立以来，乐备实不断寻求突破，公司的服务技术平台已扩展到单细胞测序、空间多组学、流式检测、超敏电化学发光、Luminex多因子检测、抗体芯片、PCR Array、ELISA、Elispot、PLA蛋白互作、多色免疫组化、DSP空间多组学等30多个，建立起了一套涵盖基因、蛋白、细胞以及组织水平实验的完整检测体系。

 
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