三阴性乳腺癌（TNBC）被认为是最具侵袭性的乳腺癌形式之一。羟丙基-β-环糊精 (HP-β-CD) 已被用作 C 型尼曼匹克病 (NPC) 的治疗剂。然而，HP-β-CD 对 TNBC 的确切作用和机制尚不完全清楚。为了检查 HP-β-CD 对 TNBC 细胞系（特别是 4T1 和 MDA-MB-231 细胞）增殖和迁移的影响，进行了一系列测定，包括 MTT、划痕、细胞周期和克隆形成测定。此外，使用 4T1 荷瘤 BALB/c 小鼠模型体内评估了 HP-β-CD 治疗 TNBC 的有效性。我们在体外和体内证明了 HP-β-CD 对 TNBC 的抗增殖和抗迁移作用。高胆固醇饮食可以减弱 HP-β-CD 抑制的 TNBC 生长。从机制上讲，HP-β-CD 通过增加 ABCA1 和 ABCG1 介导的胆固醇逆向转运来降低肿瘤胆固醇水平。 HP-β-CD 促进 T 细胞浸润到肿瘤微环境 (TME)，并通过减少免疫检查点分子表达改善 CD8 T 细胞的耗竭。此外，HP-β-CD 通过减少 CCL2-p38MAPK-NF-κB 轴来抑制肿瘤相关巨噬细胞向 TME 的募集。 HP-β-CD 还抑制由 TGF-β 信号通路介导的 TNBC 细胞的上皮间质转化 (EMT)。总之，我们的研究表明 HP-β-CD 有效抑制了 TNBC 的增殖和转移，凸显 HP-β-CD 可能有望成为一种潜在的抗肿瘤药物。版权所有 © 2023 Elsevier B.V. 保留所有权利。

Triple negative breast cancer (TNBC) is regarded as one of the most aggressive forms of breast cancer. Hydroxypropyl-β-cyclodextrin (HP-β-CD) has been used as a therapeutic agent for Niemann-Pick disease Type C (NPC). However, the exact actions and mechanisms of HP-β-CD on TNBC are not fully understood. To examine the influence of HP-β-CD on the proliferation and migration of TNBC cell lines, particularly 4T1 and MDA-MB-231 cells, a range of assays, including MTT, scratch, cell cycle, and clonal formation assays, were performed. Furthermore, the effectiveness of HP-β-CD in the treatment of TNBC was assessed in vivo using a 4T1 tumor-bearing BALB/c mouse model. We demonstrated the anti-proliferation and anti-migration effect of HP-β-CD on TNBC both in vitro and in vivo. High cholesterol diet can attenuate HP-β-CD-inhibited TNBC growth. Mechanistically, HP-β-CD reduced tumor cholesterol levels by increasing ABCA1 and ABCG1-mediated cholesterol reverse transport. HP-β-CD promoted the infiltration of T cells into the tumor microenvironment (TME) and improved exhaustion of CD8+ T cells via reducing immunological checkpoint molecules expression. Additionally, HP-β-CD inhibited the recruitment of tumor associated macrophages to the TME via reducing CCL2-p38MAPK-NF-κB axis. HP-β-CD also inhibited the epithelial mesenchymal transition (EMT) of TNBC cells mediated by the TGF-β signaling pathway. In summary, our study suggests that HP-β-CD effectively inhibited the proliferation and metastasis of TNBC, highlighting HP-β-CD may hold promise as a potential antitumor drug.Copyright © 2023 Elsevier B.V. All rights reserved.