文章：

LMP7特异性抑制剂M3258调节三阴性乳腺癌和炎性乳腺癌的肿瘤微环境

LMP7-Specific Inhibitor M3258 Modulates the Tumor Microenvironment of Triple-Negative Breast Cancer and Inflammatory Breast Cancer

原文发布日期：4 June 2025

DOI: 10.3390/cancers17111887

类型: Article

开放获取: 是

英文摘要：

Triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) are the most aggressive molecular subtypes of breast cancer. Poor clinical outcomes highlight the pressing need to discover novel targets for the effective treatment of these diseases. LMP7 (β5i/PSMB8), a proteolytic subunit of the immunoproteasome, is implicated in the pathogenesis of multiple myeloma, autoimmune and inflammatory diseases, and inflammation-related cancers. However, the role of LMP7 in TNBC and IBC remains poorly characterized. Here, we evaluated the function of LMP7 in TNBC and IBC using the selective LMP7 inhibitor M3258. In human TNBC patient samples, LMP7 expression correlated strongly with CD8+T cell infiltration and activation markers. M3258 inhibited LMP7 activity, reduced viability, and induced apoptosis in TNBC/IBC cell lines in vitro. In a novel immunocompetent in vivo model of TNBC/IBC, M3258 reduced tumor growth and the tumor abundance of M2 macrophages. Additionally, M3258 activated tumor-infiltrating CD8+T cells and suppressed the expression of specific inflammatory pathway gene signatures in immune cells. Co-culture with M2 macrophages enhanced the invasiveness of TNBC/IBC cells, which was effectively suppressed by M3258 treatment. Our results demonstrate for the first time that LMP7 shapes the pro-tumorigenic microenvironment of TNBC/IBC, in part by modulating the pathogenic role of M2 macrophages. These findings suggest that LMP7 may represent a novel target for therapeutic intervention in TNBC/IBC.

摘要翻译： 

三阴性乳腺癌（TNBC）和炎性乳腺癌（IBC）是乳腺癌中侵袭性最强的分子亚型。其不良的临床预后凸显了寻找有效治疗新靶点的迫切需求。LMP7（β5i/PSMB8）作为免疫蛋白酶体的水解亚基，已被证实与多发性骨髓瘤、自身免疫性疾病、炎症性疾病及炎症相关癌症的发病机制相关。然而，LMP7在TNBC和IBC中的作用尚不明确。本研究采用选择性LMP7抑制剂M3258，系统评估了LMP7在TNBC和IBC中的功能。在人类TNBC患者样本中，LMP7表达与CD8⁺ T细胞浸润及活化标志物呈显著正相关。体外实验表明，M3258能有效抑制LMP7活性，降低TNBC/IBC细胞系的活力并诱导其凋亡。在新型免疫健全的TNBC/IBC体内模型中，M3258显著抑制肿瘤生长并减少M2型巨噬细胞的肿瘤浸润。此外，M3258能激活肿瘤浸润性CD8⁺ T细胞，并抑制免疫细胞中特定炎症通路基因标志物的表达。共培养实验显示，M2型巨噬细胞可增强TNBC/IBC细胞的侵袭能力，而M3258处理能有效抑制此效应。我们的研究首次证明，LMP7通过调控M2型巨噬细胞的致病作用，参与塑造TNBC/IBC的促肿瘤微环境。这些发现提示，LMP7可能成为TNBC/IBC治疗干预的新靶点。

原文链接：

LMP7-Specific Inhibitor M3258 Modulates the Tumor Microenvironment of Triple-Negative Breast Cancer and Inflammatory Breast Cancer