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<p>The peritumoural adipose tissue (PAT) is a key contributor to cancer therapy resistance, yet its role in regulating ferroptosis remains unclear. Here we demonstrate that PAT confers ferroptosis resistance to cancer cells by upregulating ferritin (FTH1/FTL) and sequestering intracellular iron. PAT-derived kynurenine (KYN) was identified as the principal mediator. KYN is taken up by cancer cells and metabolized to 3-hydroxykynurenine, which directly binds to nuclear receptor coactivator 4 (NCOA4). This interaction inhibits NCOA4-mediated ferritinophagy, preventing ferritin degradation and limiting the free iron pool required for ferroptosis. In murine models, pharmacological inhibition of the KYN pathway synergized with PD-1 blockade to overcome ferroptosis resistance and suppress tumour progression. These findings reveal a PAT–KYN–ferritinophagy axis that promotes ferroptosis resistance, highlighting the potential of targeting adipose–tumour cross-talk to enhance immunotherapy in PAT-associated tumours.</p>

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Peritumoural adipose tissue promotes ferroptosis resistance by 3-hydroxykynurenine-mediated suppression of ferritinophagy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月11日

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  • Yan-Yu Zhang,
  • Yi Han,
  • Yue-Tao Tan,
  • Yun-Xin Lu,
  • Meng-Yao Ma,
  • Yong-Qiang Zheng,
  • Hao-Jie Chen,
  • Hai-Yan Fu,
  • Hai-Yu Mo,
  • Qi-Nian Wu,
  • Xiao-Jing Luo,
  • Kun Liao,
  • Wen-Qi Chen,
  • Zhao-Lei Zeng,
  • Hai-Long Piao,
  • Hong-Li Du,
  • Jun-Zhong Lin,
  • Tian Tian,
  • Rui-Hua Xu,
  • Huai-Qiang Ju

摘要

The peritumoural adipose tissue (PAT) is a key contributor to cancer therapy resistance, yet its role in regulating ferroptosis remains unclear. Here we demonstrate that PAT confers ferroptosis resistance to cancer cells by upregulating ferritin (FTH1/FTL) and sequestering intracellular iron. PAT-derived kynurenine (KYN) was identified as the principal mediator. KYN is taken up by cancer cells and metabolized to 3-hydroxykynurenine, which directly binds to nuclear receptor coactivator 4 (NCOA4). This interaction inhibits NCOA4-mediated ferritinophagy, preventing ferritin degradation and limiting the free iron pool required for ferroptosis. In murine models, pharmacological inhibition of the KYN pathway synergized with PD-1 blockade to overcome ferroptosis resistance and suppress tumour progression. These findings reveal a PAT–KYN–ferritinophagy axis that promotes ferroptosis resistance, highlighting the potential of targeting adipose–tumour cross-talk to enhance immunotherapy in PAT-associated tumours.