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
  • 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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