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<p>Tumor metastasis is the primary cause of cancer treatment failure and mortality. Pregnant patients with cancer sometimes experience a poor prognosis and accelerated disease progression, yet the underlying mechanisms remain poorly understood. Here we show that pregnancy enhances tumor metastasis in female mice by elevating adenosine levels, which drives pre-metastatic niche remodeling. Myeloid cells in placental and uterine tissues exhibit increased expression of adenosine-generating enzymes, CD39 and CD73. The accumulated adenosine recruits neutrophils into the tissues of the pre-metastatic microenvironment and upregulates PD-L1 expression on these cells through the cAMP-PKA-NF-κB pathway, thereby suppressing CD8<sup>+</sup> T cell function. Consistent with murine models, pregnant women exhibit elevated adenosine levels and increased PD-L1<sup>+</sup> neutrophils in peripheral blood, hindering human T cell activation. Inhibiting the adenosine-PD-L1<sup>+</sup> neutrophil axis reverses, at least partially, pregnancy-accelerated metastasis without affecting fetal development. These findings shed light on the mechanism of tumor metastasis mice during pregnancy and suggest potential therapeutic targets for treating cancers in pregnant patients.</p>

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Pregnancy promotes tumor metastasis through adenosine-induced immunosuppressive neutrophils in pre-metastatic microenvironment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月4日

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  • Chen Chen,
  • Jiahong Shi,
  • Yutiantian Lei,
  • Qian Wang,
  • Peihai Cao,
  • Dairu Hou,
  • Mengdi Huang,
  • Ruiying Wang,
  • Qiuyu Mu,
  • Tingting Lv,
  • Rui Jia,
  • Mingjun Si,
  • Dingge Jiang,
  • Lei Li,
  • Zhixuan Cai,
  • Yakun Huang,
  • Jiahao Sun,
  • Lianying Jiao,
  • Zhengtao Xiao,
  • Yuhan Li,
  • Binxian Wang,
  • Shan Huang,
  • Wenqian Du,
  • Lu Bai,
  • Jinlu Ma,
  • Suxia Han,
  • Baojun Zhang,
  • Chen Lin,
  • Hui Guo,
  • Xiangjiao Meng,
  • Yuzhu Hou

摘要

Tumor metastasis is the primary cause of cancer treatment failure and mortality. Pregnant patients with cancer sometimes experience a poor prognosis and accelerated disease progression, yet the underlying mechanisms remain poorly understood. Here we show that pregnancy enhances tumor metastasis in female mice by elevating adenosine levels, which drives pre-metastatic niche remodeling. Myeloid cells in placental and uterine tissues exhibit increased expression of adenosine-generating enzymes, CD39 and CD73. The accumulated adenosine recruits neutrophils into the tissues of the pre-metastatic microenvironment and upregulates PD-L1 expression on these cells through the cAMP-PKA-NF-κB pathway, thereby suppressing CD8+ T cell function. Consistent with murine models, pregnant women exhibit elevated adenosine levels and increased PD-L1+ neutrophils in peripheral blood, hindering human T cell activation. Inhibiting the adenosine-PD-L1+ neutrophil axis reverses, at least partially, pregnancy-accelerated metastasis without affecting fetal development. These findings shed light on the mechanism of tumor metastasis mice during pregnancy and suggest potential therapeutic targets for treating cancers in pregnant patients.