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

作者：Yan-Yu Zhang, Yi Han, Yue-Tao Tan, Yun-Xin Lu, Meng-Yao Ma, Yongqiang Zheng, Haojie Chen, Haiyan Fu, Hai-Yu Mo, Qi Wu, Xiao-Jing Luo, Kun Liao, Wenqi Chen, Zhao-Lei Zeng, Hai-Long Piao, Hong-Li Du, Jun-Zhong Lin, Tian Tian, Rui-Hua Xu, Huai‐Qiang Ju · 发表于：Nature Cell Biology · 年份：2026 · DOI：10.1038/s41556-026-01907-x · 被引用次数：3 · 研究领域：Ferroptosis and cancer prognosis、Autophagy in Disease and Therapy、Iron Metabolism and Disorders

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.