2. Academic Validation
  3. Hypoxia-inducible factor orchestrates adenosine metabolism to promote liver cancer development

Hypoxia-inducible factor orchestrates adenosine metabolism to promote liver cancer development

  • Sci Adv. 2023 May 5;9(18):eade5111. doi: 10.1126/sciadv.ade5111.
Jacinth Wing-Sum Cheu 1 2,  David Kung-Chun Chiu 1,  Kenneth Kin-Leung Kwan 1 2,  Chunxue Yang 1,  Vincent Wai-Hin Yuen 1 2,  Chi Ching Goh 1,  Noreen Nog-Qin Chui 1,  Wei Shen 1 2,  Cheuk-Ting Law 1,  Qidong Li 1,  Misty Shuo Zhang 1 2,  Macus Hao-Ran Bao 1 2,  Bowie Po-Yee Wong 1,  Cerise Yuen-Ki Chan 1 2,  Cindy Xinqi Liu 1,  Grace Fu-Wan Sit 1,  Zher Yee Ooi 1,  Haijing Deng 1,  Aki Pui-Wah Tse 1 2,  Irene Oi-Lin Ng 1 3,  Carmen Chak-Lui Wong 1 2 3 4 5
Affiliations

Affiliations

  • 1 Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
  • 2 Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong.
  • 3 State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong.
  • 4 Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen University, Guangzhou, China 510120.
  • 5 Shenzhen Hospital, The University of Hong Kong, Shenzhen, China.
PMID: 37146141 DOI: 10.1126/sciadv.ade5111
Abstract

Hypoxia-induced adenosine creates an immunosuppressive tumor microenvironment (TME) and dampens the efficacy of immune checkpoint inhibitors (ICIs). We found that hypoxia-inducible factor 1 (HIF-1) orchestrates adenosine efflux through two steps in hepatocellular carcinoma (HCC). First, HIF-1 activates transcriptional repressor MXI1, which inhibits Adenosine Kinase (ADK), resulting in the failure of adenosine phosphorylation to adenosine monophosphate. This leads to adenosine accumulation in hypoxic Cancer cells. Second, HIF-1 transcriptionally activates equilibrative nucleoside transporter 4, pumping adenosine into the interstitial space of HCC, elevating extracellular adenosine levels. Multiple in vitro assays demonstrated the immunosuppressive role of adenosine on T cells and myeloid cells. Knockout of ADK in vivo skewed intratumoral immune cells to protumorigenic and promoted tumor progression. Therapeutically, combination treatment of Adenosine Receptor antagonists and anti-PD-1 prolonged survival of HCC-bearing mice. We illustrated the dual role of hypoxia in establishing an adenosine-mediated immunosuppressive TME and offered a potential therapeutic approach that synergizes with ICIs in HCC.

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