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Peritumoural adipose tissue promotes ferroptosis resistance by 3-hydroxykynurenine-mediated suppression of ferritinophagy
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DOI：10.1038/s41556-026-01907-x.png)
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Abstract
En 中文
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. Zhang, Han, Tan, Lu, Ma et al. report that kynurenine derived from peritumoural adipose tissue is hijacked by cancer cells to mediate ferroptosis resistance, a process that could potentially be targeted with immunotherapy to inhibit tumour growth.
Keywords:
Cancer immunotherapy
Cancer metabolism
Cancer microenvironment
Cell death
Life Sciences
general
Cell Biology
Cancer Research
Developmental Biology
Stem Cells
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