2. Academic Validation
  3. Peritumoural adipose tissue promotes ferroptosis resistance by 3-hydroxykynurenine-mediated suppression of ferritinophagy

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

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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