The Adenosine Pathway: CD39, CD73 and A2A Receptors

The Enzyme Cascade

The ectoenzyme CD39 removes phosphates from extracellular ATP to make AMP, and CD73 then removes the last phosphate to make adenosine. Both enzymes are expressed on many tumour cells, on regulatory T cells and on suppressive myeloid cells.

The result is a shift from a pro-inflammatory ATP-rich environment to an anti-inflammatory adenosine-rich one, concentrated where it does the tumour most good.

How Adenosine Suppresses Immunity

Adenosine acts mainly through the A2A receptor on T cells and natural killer cells. Receptor engagement raises intracellular cyclic AMP, which blunts T-cell-receptor signalling, reduces cytokine production and cytotoxicity, and favours regulatory over effector differentiation.

Hypoxia amplifies the whole pathway: HIF-1 increases CD73 expression and adenosine production, linking the poorly oxygenated tumour core to local immune suppression.

Therapeutic Status

CD73 antibodies, CD39 inhibitors and small-molecule A2A receptor antagonists have been tested, mostly in combination with PD-1 blockade. Some early trials showed signals of activity, particularly in tumours with high adenosine-pathway gene expression, but no agent in this class is approved.

An adenosine gene-expression signature has been explored as a way to select patients, though it is not a validated companion diagnostic.

Why the Pathway Is Still Pursued

Despite trial setbacks, the adenosine axis remains attractive because it is a convergence point: hypoxia, CD73-high tumours, regulatory T cells and ATP release from dying cells all feed it, so blocking it could relieve several suppressive inputs at once. Subgroups with high adenosine-signature expression have shown the clearest signals, which is shaping how newer trials enrol.

The likely place for these drugs, if any, is in combinations — with PD-1 blockade, with agents that increase ATP release such as chemotherapy or radiotherapy, or with treatments that reduce hypoxia. None is approved, and an adenosine gene-expression signature is a research selection tool rather than a validated diagnostic.

Key Takeaways

• ·CD39 and CD73 convert immune-activating ATP into immune-suppressing adenosine in the tumour.
• ·Adenosine acts through the A2A receptor to dampen T-cell and natural killer cell function, and hypoxia amplifies it.
• ·Drugs against CD73, CD39 and A2A are in trials, mainly with checkpoint inhibitors, but none is approved.