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<p>Interleukin-33 (IL-33) plays multifaceted roles in tumor progression, but its autocrine regulation of breast cancer stemness and metastasis via the Wnt pathway remains unclear. Here, we investigated the IL-33/ST2 axis in breast cancer using CRISPR/Cas9, single-cell RNA sequencing, and murine models (orthotopic 4T1 and spontaneous MMTV-PyMT). Elevated IL-33 levels correlated with aggressive subtypes and poor prognosis. IL-33 overexpression enhanced proliferation, migration, and cancer stem cell (CSC) marker expression (CD44, ALDH1) in 4T1 and MDA-MB-231 cells, whereas ST2 knockdown via CRISPR or adeno-associated virus (AAV) attenuated tumor growth and metastasis in vivo, reducing CSC frequency. Mechanistically, IL-33 activated Wnt/β-catenin signaling to promote stemness, which was reversed by the Wnt inhibitor XAV-939. Single-cell analysis revealed that IL-33 overexpression skewed the immune microenvironment toward immunosuppression, while ST2 knockdown restored antitumor immunity. Our findings establish an IL-33–Wnt axis as a critical driver of breast cancer aggressiveness and propose AAV-mediated ST2 silencing as a novel therapeutic strategy. Targeting this axis may offer dual benefits by suppressing stemness and enhancing immune surveillance, warranting clinical exploration for advanced breast cancer.</p>

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Targeting of the IL-33/Wnt axis restricts breast cancer stemness and metastasis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月25日

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  • Guanglin Fan,
  • Shuting Zuo,
  • Zhen Wang,
  • Siwei Zhang,
  • Liping Liu,
  • Haoge Luo,
  • Yingdong Xie,
  • Yan Zhang,
  • Dong Li

摘要

Interleukin-33 (IL-33) plays multifaceted roles in tumor progression, but its autocrine regulation of breast cancer stemness and metastasis via the Wnt pathway remains unclear. Here, we investigated the IL-33/ST2 axis in breast cancer using CRISPR/Cas9, single-cell RNA sequencing, and murine models (orthotopic 4T1 and spontaneous MMTV-PyMT). Elevated IL-33 levels correlated with aggressive subtypes and poor prognosis. IL-33 overexpression enhanced proliferation, migration, and cancer stem cell (CSC) marker expression (CD44, ALDH1) in 4T1 and MDA-MB-231 cells, whereas ST2 knockdown via CRISPR or adeno-associated virus (AAV) attenuated tumor growth and metastasis in vivo, reducing CSC frequency. Mechanistically, IL-33 activated Wnt/β-catenin signaling to promote stemness, which was reversed by the Wnt inhibitor XAV-939. Single-cell analysis revealed that IL-33 overexpression skewed the immune microenvironment toward immunosuppression, while ST2 knockdown restored antitumor immunity. Our findings establish an IL-33–Wnt axis as a critical driver of breast cancer aggressiveness and propose AAV-mediated ST2 silencing as a novel therapeutic strategy. Targeting this axis may offer dual benefits by suppressing stemness and enhancing immune surveillance, warranting clinical exploration for advanced breast cancer.