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

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.

CRABP2 affects chemotherapy resistance of ovarian cancer by regulating the expression of HIF1α

“…HIF1α promotes the utilization of glucose and oxygen by tumor cells, and increases the activity of oxidative phosphorylation and tricarboxylic acid cycling [ 36 ]. In addition, HIF1α is also involved in the regulation of lipid metabolism and amino acid metabolism in tumor cells [ 37 – 40 ]. The studies also found that by interfering with the activity of HIF1α, it can inhibit the metabolic reprogramming of tumor cells and improve the sensitivity of tumors to chemotherapy drugs [ 41 – 44 ].…”

Iron deficiency affects oxygen transport and activates HIF1 signaling pathway to regulate phenotypic transformation of VSMC in aortic dissection

“…The results show that ID can promote the increase of ROS content in cells, while HIF1 plays a role as a transcription factor that is stimulated by hypoxic environment and its expression is increased (Waypa and Schumacker 2019 ; Cheu et al 2023 ). When the aorta is in ID and subjected to external stimulation such as AngII, it will rapidly promote the phenotypic transformation of cells, resulting in increased disease occurrence and expanded lesion involvement.…”

Metabolic reprogramming in the tumor microenvironment of liver cancer

“…In HCC cells, hypoxia contributes to adenosine accumulation and extracellular secretion. This results in adenosine-mediated immunosuppressive roles on T cells and myeloid cells [ 149 , 150 ]. Tumor cell-derived adenosine also synergizes with autocrine granulocyte–macrophage colony-stimulating factor (GM-CSF) secreted from activated TAM to promote their proliferation, thus maintaining the Mφ pools in HCC [ 151 ].…”