AhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer

Zikun Ma, Zhiyong Li, Yize Mao, Jingwei Ye, Zefu Liu, Yuzhao Wang, Chen Wei, Jun Cui (), Zhuowei Liu () and Xiaoyu Liang ()
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Zikun Ma: Sun Yat-sen University Cancer Center
Zhiyong Li: Sun Yat-sen University Cancer Center
Yize Mao: Sun Yat-sen University Cancer Center
Jingwei Ye: Sun Yat-sen University Cancer Center
Zefu Liu: Central South University
Yuzhao Wang: Sun Yat-sen University Cancer Center
Chen Wei: University of Chinese Academy of Sciences
Jun Cui: Sun Yat-sen University
Zhuowei Liu: Sun Yat-sen University Cancer Center
Xiaoyu Liang: Sun Yat-sen University Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract The induction of type-I interferons (IFN-Is) is important for the efficacy of chemotherapy. By investigating the role of amino acids in regulation of IFN-I production under chemo-drug treatment in bladder cancer (BC) cells, we find an inherent AhR-dependent negative feedback to restrain STING signaling and IFN-I production. Mechanistically, in a ligand dependent manner, AhR bridges STING and CUL4B/RBX1 E3 ligase complex, facilitating STING degradation through ubiquitin-proteasome pathway. Inhibition of AhR increases STING levels and reduces tumor growth under cisplatin or STING agonist treatment. Endogenous AhR ligands are mainly consisted of tryptophan (Trp) metabolites; dietary Trp restriction, blocking the key Trp metabolism rate-limiting enzyme IDO1 or inhibition of cellular Trp importation also show similar effect as AhR inhibition. Clinically, BC patients with higher intratumoral expression of AhR or stronger intratumoral Trp metabolism (higher IDO1 or Kyn levels) that lead to higher AhR activation show worse response rate to neoadjuvant chemotherapy (NAC).

Date: 2023
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DOI: 10.1038/s41467-023-41218-5

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