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. 2023 May 17;24(10):8871. doi: 10.3390/ijms24108871

Figure 1.

Figure 1

Sources of Adenosine in the TME. The major adenosine (eADO)-producing pathway in the TME involves the processing of the precursor ATP by ectonucleotidases. ATP is released into the extracellular environment due to cell death. ATP accumulating in the extracellular milieu is then enzymatically converted via the canonical pathway involving the sequential hydrolysis of ATP to ADP and AMP by CD39 and subsequently the hydrolysis of AMP to eADO by CD73. In the non-canonical pathway, precursor NAD+ substrate is acted on by CD38 to generate ADP-ribose (ADPR) that can be converted to AMP by CD203a, which is then hydrolyzed by CD73 to produce eADO. To reduce eADO levels in the extracellular space, adenosine can be re-uptaken into the cell via nucleoside transporters, where it is converted to AMP by ADO kinase or converted to inosine by cell surface ADO deaminase. Hypoxic signaling in tumor cells promotes expression of CD39 and CD73 while simultaneously inhibiting ADO kinase and ADO deaminase activity. Created with BioRender.com.