Department of Breast Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhua Xi Road, Jinan, Shandong 250012, China.
Department of Breast Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhua Xi Road, Jinan, Shandong 250012, China; Department of Pathology Tissue Bank, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhua Xi Road, Jinan, Shandong 250012, China; Research Institute of Breast Cancer, Shandong University, 107 Wenhua Xi Road, Jinan, Shandong 250012, China.
Phytomedicine. 2024 Dec;135:156051. doi: 10.1016/j.phymed.2024.156051. Epub 2024 Sep 13.
Triple-negative breast cancer (TNBC) is the most intractable subgroup of breast neoplasms due to its aggressive nature. In recent years, immune checkpoint inhibitors (ICIs) have exhibited potential efficacy in TNBC treatment. However, only a limited fraction of patients benefit from ICI therapy, primarily because of the suppressive tumor immune microenvironment (TIME). Trametes robiniophila Murr (Huaier) is a traditional Chinese medicine (TCM) with potential immunoregulatory functions. However, the underlying mechanism remains unclear.
The present study aimed to investigate the therapeutic role of Huaier in the TIME of TNBC patients.
Single-cell RNA sequencing (scRNA-seq) was used to systematically analyze the influence of Huaier on the TNBC microenvironment for the first time. The mechanisms of the Huaier-induced suppression of cancer-associated fibroblasts (CAFs) were assessed via real-time quantitative polymerase chain reaction (qRT‒PCR) and western blotting. A tumor-bearing mouse model was established to verify the effects of the oral administration of Huaier on immune infiltration.
Unsupervised clustering of the transcriptional profiles suggested an increase in the number of apoptotic cancer cells in the Huaier group. Treatment with Huaier induced immunological alterations from a "cold" to a "hot" state, which was accompanied by phenotypic changes in CAFs. Mechanistic analysis revealed that Huaier considerably attenuated the formation of myofibroblastic CAFs (myoCAFs) by impairing transforming growth factor-beta (TGF-β)/SMAD signaling. In mouse xenograft models, Huaier dramatically modulated CAF differentiation, thus synergizing with the programmed cell death 1 (PD1) blockade to impede tumor progression.
Our findings demonstrate that Huaier regulates cancer immunity in TNBC by suppressing the transition of CAFs to myoCAFs and emphasize the crucial role of Huaier as an effective adjuvant agent in immunotherapy.
三阴性乳腺癌（TNBC）因其侵袭性强，是最棘手的乳腺癌亚组。近年来，免疫检查点抑制剂（ICI）在 TNBC 治疗中显示出潜在疗效。然而，只有有限比例的患者受益于 ICI 治疗，主要是因为肿瘤免疫微环境（TIME）受到抑制。云芝是一种具有潜在免疫调节功能的中药。然而，其潜在机制尚不清楚。
本研究旨在探讨云芝在 TNBC 患者 TIME 中的治疗作用。
首次利用单细胞 RNA 测序（scRNA-seq）系统分析云芝对 TNBC 微环境的影响。通过实时定量聚合酶链反应（qRT-PCR）和蛋白质印迹法评估云芝诱导的癌症相关成纤维细胞（CAFs）抑制的机制。建立荷瘤小鼠模型，验证云芝口服给药对免疫浸润的影响。
无监督聚类分析转录谱表明，云芝组癌细胞凋亡数量增加。云芝治疗诱导免疫状态从“冷”变为“热”，同时 CAFs 表型发生变化。机制分析表明，云芝通过抑制转化生长因子-β（TGF-β）/SMAD 信号通路，显著削弱肌成纤维 CAFs（myoCAFs）的形成。在小鼠异种移植模型中，云芝显著调节 CAF 分化，与程序性细胞死亡蛋白 1（PD1）阻断协同抑制肿瘤进展。
我们的研究结果表明，云芝通过抑制 CAFs 向 myoCAFs 的转化来调节 TNBC 中的癌症免疫，并强调了云芝作为免疫治疗有效佐剂的关键作用。
