2. Academic Validation
  3. Quercetin-derived microbial metabolite DOPAC potentiates CD8+ T cell anti-tumor immunity via NRF2-mediated mitophagy

Quercetin-derived microbial metabolite DOPAC potentiates CD8+ T cell anti-tumor immunity via NRF2-mediated mitophagy

  • Cell Metab. 2025 Oct 24:S1550-4131(25)00395-X. doi: 10.1016/j.cmet.2025.09.010.
Penghu Han 1,  Shuzheng Chu 2,  Jing Shen 1,  Lixiang Li 3,  Yan Zhang 4,  Shiguan Wang 5,  Yatai Chen 1,  Yangchun Ma 6,  Xiaolong Tang 7,  Chao Gao 8,  Xiangyun Zheng 9,  Bowen Xu 1,  Qiong Wang 10,  Detian Yuan 11,  Shiyang Li 12
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Qilu Hospital of Shandong University, Advanced Medical Research Institute, Shandong University, Jinan 250012, China.
  • 2 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China.
  • 3 Department of Gastroenterology, Qilu Hospital of Shandong University, Advanced Medical Research Institute, Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Digestive Diseases, Qilu Hospital of Shandong University, Jinan 250012, China.
  • 4 Department of Diagnostics, Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
  • 5 Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012, China.
  • 6 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), Cheeloo College of Medicine Shandong University, Jinan 250012, China.
  • 7 Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, China.
  • 8 Department of Hepatobiliary Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan 250012, China.
  • 9 Department of Colorectal and Anal Surgery, Weihai Municipal Hospital of Shandong University, Weihai 264200, China.
  • 10 Sichuan Anaerobic Biotechnology, Chengdu 610000, China.
  • 11 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China. Electronic address: yuandt@sdu.edu.cn.
  • 12 Department of Gastroenterology, Qilu Hospital of Shandong University, Advanced Medical Research Institute, Shandong University, Jinan 250012, China; Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan 250012, China. Electronic address: lishiyang@sdu.edu.cn.
PMID: 41138722 DOI: 10.1016/j.cmet.2025.09.010
Abstract

Quercetin, a dietary flavonol, shows promise in Cancer prevention, though its effects on the immune compartment within the tumor microenvironment are not fully understood. Here, we identify 3,4-dihydroxyphenylacetic acid (DOPAC), a microbial metabolite of quercetin, as a critical mediator of its anti-tumor effects in a CD8+ T cell-dependent manner. Mechanistically, DOPAC directly binds to Kelch-like epichlorohydrin-associated protein 1 (KEAP1), disrupting its interaction with nuclear factor erythroid 2-related factor 2 (NRF2) and preventing KEAP1-mediated degradation of NRF2 in CD8+ T cells. Elevated NRF2 transcriptionally enhances the expression of B cell lymphoma 2-interacting protein 3, promoting Mitophagy and mitochondrial functionality, which improves CD8+ T cell fitness within the tumor microenvironment. Furthermore, DOPAC synergizes with immune checkpoint blockade to suppress tumor growth. Our findings underscore the role of microbial metabolites of dietary nutrients in modulating anti-tumor immune responses, positioning DOPAC as a promising candidate for Cancer Immunotherapy.

Keywords

BNIP3; CD8(+) T cells; DOPAC; NRF2; anti-tumor immunity; microbiota; mitophgagy; quercetin.

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