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<p>Bone metastasis is a lethal consequence of breast cancer. AT-rich interaction domain 1 A gene (<i>ARID1A</i>), a subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, regulates immunosuppressive tumor microenvironment. However, its specific role in bone metastasis remains unclear. Here, we show that female patients with <i>ARID1A</i>‑mutated triple negative breast cancer (TNBC) exhibit a higher bone metastasis incidence. Most <i>ARID1A</i> mutations result in loss of protein expression. <i>ARID1A</i> deficiency upregulates the arginine metabolic pathway, increasing ornithine and spermine levels that promote the expansion of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) within the bone marrow, thereby facilitating bone metastasis. Targeting key enzymes of arginase 2 (ARG2) and ornithine decarboxylase 1 (ODC1) in arginine metabolic pathway effectively reduces bone metastasis in <i>ARID1A</i>-deficient models. Collectively, these findings reveal that <i>ARID1A</i> deficiency promotes bone metastasis by activating arginine metabolism to expand PMN-MDSCs and potentially offers therapeutic strategies for preventing bone metastasis in female patients with <i>ARID1A</i>-deficient TNBC.</p>

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Targeting arginine metabolism reverses bone immunosuppressive microenvironment and metastasis in ARID1A-deficient triple negative breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • Shuangyue Pan,
  • Jinyan Wang,
  • Boya Wang,
  • Fangqian Wang,
  • Qingjian Chen,
  • Tiantian Liu,
  • Aima Zhang,
  • Shenyuqi Wu,
  • Bin Li,
  • Hai Hu,
  • Mengdi Yang,
  • Zhonghua Tao,
  • Xichun Hu

摘要

Bone metastasis is a lethal consequence of breast cancer. AT-rich interaction domain 1 A gene (ARID1A), a subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, regulates immunosuppressive tumor microenvironment. However, its specific role in bone metastasis remains unclear. Here, we show that female patients with ARID1A‑mutated triple negative breast cancer (TNBC) exhibit a higher bone metastasis incidence. Most ARID1A mutations result in loss of protein expression. ARID1A deficiency upregulates the arginine metabolic pathway, increasing ornithine and spermine levels that promote the expansion of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) within the bone marrow, thereby facilitating bone metastasis. Targeting key enzymes of arginase 2 (ARG2) and ornithine decarboxylase 1 (ODC1) in arginine metabolic pathway effectively reduces bone metastasis in ARID1A-deficient models. Collectively, these findings reveal that ARID1A deficiency promotes bone metastasis by activating arginine metabolism to expand PMN-MDSCs and potentially offers therapeutic strategies for preventing bone metastasis in female patients with ARID1A-deficient TNBC.