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

  • Nat Cell Biol. 2026 Apr;28(4):783-796. doi: 10.1038/s41556-026-01907-x.
Yan-Yu Zhang  #  1 ,  Yi Han  #  1  2 ,  Yue-Tao Tan  #  3 ,  Yun-Xin Lu  #  1 ,  Meng-Yao Ma  #  4 ,  Yong-Qiang Zheng  1 ,  Hao-Jie Chen  1 ,  Hai-Yan Fu  1 ,  Hai-Yu Mo  1 ,  Qi-Nian Wu  1 ,  Xiao-Jing Luo  1 ,  Kun Liao  1 ,  Wen-Qi Chen  5 ,  Zhao-Lei Zeng  1 ,  Hai-Long Piao  6 ,  Hong-Li Du  7 ,  Jun-Zhong Lin  1 ,  Tian Tian  8 ,  Rui-Hua Xu  9 ,  Huai-Qiang Ju  10  11
Affiliations
  • 1. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.
  • 2. Cancer microbiome platform, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.
  • 3. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, People's Republic of China.
  • 4. Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, People's Republic of China.
  • 5. Department of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, People's Republic of China.
  • 6. CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, People's Republic of China.
  • 7. School of Biology and Biological Engineering, South China University of Technology, Guangzhou, People's Republic of China.
  • 8. Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, People's Republic of China. [email protected].
  • 9. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China. [email protected].
  • 10. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China. [email protected].
  • 11. Department of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 41813885 DOI: 10.1038/s41556-026-01907-x
Abstract

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.

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