2. Academic Validation
  3. Huaier-induced suppression of cancer-associated fibroblasts confers immunotherapeutic sensitivity in triple-negative breast cancer

Huaier-induced suppression of cancer-associated fibroblasts confers immunotherapeutic sensitivity in triple-negative breast cancer

  • Phytomedicine. 2024 Sep 13:135:156051. doi: 10.1016/j.phymed.2024.156051.
Chen Li 1,  Xiaolong Wang 1,  Luyao Xing 1,  Tong Chen 1,  Wenhao Li 1,  Xin Li 1,  Yifei Wang 1,  Chao Yang 1,  Qifeng Yang 2
Affiliations

Affiliations

  • 1 Department of Breast Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhua Xi Road, Jinan, Shandong 250012, China.
  • 2 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. Electronic address: qifengyang@sdu.edu.cn.
PMID: 39299097 DOI: 10.1016/j.phymed.2024.156051
Abstract

Background: 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.

Purpose: The present study aimed to investigate the therapeutic role of Huaier in the TIME of TNBC patients.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

CAF; Huaier; TGF-β; TNBC; scRNA-seq.

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