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

• Published in: Science advances Vol. 9; no. 18; p. eade5111
• Main Authors: Cheu, Jacinth Wing-Sum, Chiu, David Kung-Chun, Kwan, Kenneth Kin-Leung, Yang, Chunxue, Yuen, Vincent Wai-Hin, Goh, Chi Ching, Chui, Noreen Nog-Qin, Shen, Wei, Law, Cheuk-Ting, Li, Qidong, Zhang, Misty Shuo, Bao, Macus Hao-Ran, Wong, Bowie Po-Yee, Chan, Cerise Yuen-Ki, Liu, Cindy Xinqi, Sit, Grace Fu-Wan, Ooi, Zher Yee, Deng, Haijing, Tse, Aki Pui-Wah, Ng, Irene Oi-Lin, Wong, Carmen Chak-Lui
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 05.05.2023
• Subjects: Adenosine - metabolism; Animals; Biomedicine and Life Sciences; Cancer; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Hypoxia - metabolism; Immunology; Liver Neoplasms - pathology; Mice; Mice, Knockout; SciAdv r-articles; Tumor Microenvironment
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.ade5111

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.