2. Academic Validation
  3. ISLR knockdown enhances radiotherapy-induced anti-tumor immunity by disrupting the Treg-mregDC-lymphoid niche in triple-negative breast cancer

ISLR knockdown enhances radiotherapy-induced anti-tumor immunity by disrupting the Treg-mregDC-lymphoid niche in triple-negative breast cancer

  • Int Immunopharmacol. 2025 Aug 28:161:114988. doi: 10.1016/j.intimp.2025.114988.
Shuai Wang 1,  Yang Wang 2,  Yulan Bu 3,  Xuxin Duan 3,  Xiangxiang Guo 3,  Wenliang Wu 4,  Houfa Ning 5
Affiliations

Affiliations

  • 1 Department of Radiotherapy, Affiliated Hospital of Shandong Second Medical University, Weifang 261035, Shandong, China; School of Medical Imaging, Shandong Second Medical University, Weifang 261035, Shandong, China.
  • 2 Department of Oncology, Affiliated Traditional Chinese Medicine Hospital of Shandong Second Medical University,Weifang 261041, Shandong, China.
  • 3 Department of Radiotherapy, Affiliated Hospital of Shandong Second Medical University, Weifang 261035, Shandong, China.
  • 4 Department of Oncology, Affiliated Changle People's Hospital of Shandong Second Medical University, Weifang 262400, Shandong, China. Electronic address: sdwftcmws2022@163.com.
  • 5 School of Medical Imaging, Shandong Second Medical University, Weifang 261035, Shandong, China. Electronic address: ninghoufawfyx@163.com.
PMID: 40517736 DOI: 10.1016/j.intimp.2025.114988
Abstract

Background: Triple-negative breast Cancer (TNBC) is characterized by an immunosuppressive tumor microenvironment (TME) that hinders the efficacy of immunotherapy. Recent findings suggest that the interaction between ISLR and the MIF/CD74 signaling pathway plays a pivotal role in immune evasion. This study explores how radiotherapy (RT) modulates ISLR expression and its subsequent impact on immunotherapeutic outcomes in TNBC.

Methods: A multi-omics approach was employed, incorporating single-cell RNA Sequencing (scRNA-seq) and transcriptomic datasets. The role of ISLR in the MIF/CD74 signaling axis was validated in TNBC cell lines and mouse xenograft models. In vitro, ISLR expression was either knocked down or overexpressed in MDA-MB-231 cells, followed by exposure to RT at doses of 5 Gy or 10 Gy. Cellular proliferation, migration, and cytokine secretion were subsequently assessed. In vivo, TNBC-bearing mice received RT and/or PD-1 immune checkpoint inhibitors. Tumor growth, immune cell infiltration, and DNA damage were evaluated.

Results: RT markedly reduced ISLR expression, thereby disrupting the MIF/CD74 signaling pathway and attenuating the formation of the Treg-mregDC-lymphoid niche. ISLR knockdown led to decreased secretion of IL-10 and TGF-β, while promoting CD8+ T cell infiltration and enhancing anti-tumor immune responses. Mechanistic studies revealed that ISLR directly interacts with CD74 and regulates its transcriptional activity. In vivo, ISLR knockdown in combination with RT significantly suppressed tumor growth and improved the efficacy of PD-1 blockade.

Conclusions: ISLR serves as a crucial regulator of immune evasion in TNBC by modulating the MIF/CD74 signaling pathway and promoting an immunosuppressive TME. Targeting ISLR amplifies the immunogenic effects of RT and enhances the response to immunotherapy, offering a promising therapeutic strategy for TNBC management.

Keywords

ISLR; MIF/CD74 signaling pathway; Radiotherapy; Triple-negative breast cancer; Tumor microenvironment.

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