Background:TNBC patients respond poorly to chemotherapy, leading to high mortality rates and a worsening prognosis. Here, we investigated the effect of M-I on TNBC tumor growth suppression and its potential mechanisms.Methods:Signaling pathways were analyzed to study the effect of M-I on TNBC cells (human MDA-MB-231 and mouse 4T1). We used orthotopic mouse models to examine the anti-tumor efficacy of M-I. Tumor volume and the status of tumor-associated macrophages (TAMs) were assessed by qRT-PCR or FACS analysis.Results:We found a significant dose- and time-dependent inhibition of TNBC cell proliferation following treatment with M-I. Cell cycle analysis revealed a shortened S phase in M-I-treated cells and downregulation of AURKA, PLK1, CDC25c, CDK1, and cyclinB1. Furthermore, M-I treatment reduced the expression of pSTAT3, cyclinD1, and c-Myc in TNBC cells. To evaluate the anti-tumor efficacy of M-I, we employed orthotopic TNBC mouse models and observed a significant reduction in tumor growth without measurable toxicity. Next, we analyzed RNA from control and M-I-treated tumors to further assess the status of TAMs and observed a significant decrease in M2-like macrophages in the M-I-treated group. Immortalized bone marrow-derived mouse macrophages (iMacs) exposed to conditioned media (CM) of TNBC cells with or without M-I treatment indicated that the M-I treated CM of TNBC cells significantly reduce the M2phenotype in iMacs. Mechanistically, we found that M-I specifically targets the IL-4/MAPK signaling axis to reduce immunosuppressive M2 macrophage polarization.Conclusions:Our study reveals a novel mechanism by which M-I inhibits TNBC cell proliferation by regulating intracellular signaling and altering TAMs in the tumor microenvironment and highlights its potential as a promising candidate for TNBC therapy.
背景：三阴性乳腺癌（TNBC）患者对化疗反应不佳，导致高死亡率及预后恶化。本研究探讨了M-I对TNBC肿瘤生长的抑制作用及其潜在机制。 方法：通过信号通路分析研究M-I对人源MDA-MB-231和小鼠4T1两种TNBC细胞系的影响。采用原位移植小鼠模型评估M-I的抗肿瘤效果，通过qRT-PCR或流式细胞术检测肿瘤体积及肿瘤相关巨噬细胞（TAMs）状态。 结果：M-I处理能显著抑制TNBC细胞增殖，且呈现剂量与时间依赖性。细胞周期分析显示M-I处理缩短了S期时长，并下调AURKA、PLK1、CDC25c、CDK1和cyclinB1表达。此外，M-I处理降低了TNBC细胞中pSTAT3、cyclinD1和c-Myc的表达水平。在原位TNBC小鼠模型中，M-I显著抑制肿瘤生长且未观察到明显毒性。通过对对照组与M-I处理组肿瘤组织的RNA分析发现，M-I处理组中M2型巨噬细胞显著减少。使用经M-I处理/未处理的TNBC细胞条件培养基培养永生化骨髓来源小鼠巨噬细胞（iMacs）的实验表明，M-I处理组的条件培养基能显著降低iMacs中M2表型表达。机制研究表明，M-I通过特异性靶向IL-4/MAPK信号轴来抑制免疫抑制性M2型巨噬细胞极化。 结论：本研究揭示了M-I通过调控细胞内信号通路及改变肿瘤微环境中TAMs状态来抑制TNBC细胞增殖的新机制，凸显其作为TNBC治疗候选药物的潜力。
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