Therapeutic potential of adenosine receptor modulators in cancer treatment

Abstract

All human cells contain the universal autocoid adenosine, which interacts with four types of G protein-coupled receptors (GPCRs), namely A₁, A_2A, A_2B, and A₃ adenosine receptors (ARs). Among these receptors, A_2A and A_2B ARs activate adenylate cyclase, while A₁ and A₃ ARs suppress the adenylate cyclase activity. Adenosine-receptor interactions play a crucial role in cancer biology by modulating the immune microenvironment, which tumors exploit to create immunosuppression that promotes their growth and metastasis. When the A_2A AR is activated on natural killer (NK) cells and T cells, it reduces their ability to carry out cytotoxic functions. This activation also encourages the formation of immune-suppressing cell types, such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), further weakening the immune response. Targeting adenosine receptors, particularly the A_2A subtype, represents a promising therapeutic strategy. By antagonizing these receptors, it may be possible to restore T cell function, helping the body to recognize and attack cancer cells more effectively. Despite recent advancements in the discovery of novel, targeted anticancer agents, these treatments have shown limited effectiveness against metastatic tumours, complicating cancer management. Moreover, developing adenosine receptor agonists or antagonists with high target selectivity and potency remains a significant challenge, as the widespread distribution of adenosine receptors throughout the body raises concerns about off-target effects and reduced therapeutic efficacy. In order to improve outcomes for patients with advanced cancer, researchers are actively investigating safer and more efficient chemotherapy substitutes. However, drugs that activate A₃ adenosine receptors and block A_2A receptors are being explored as a novel approach for cancer treatment. Monoclonal antibodies and small-molecule inhibitors targeting the CD39/CD73/A_2A AR axis are also being tested in clinical trials, both as standalone treatments and in combination with anti-PD-1/PD-L1 immunotherapies. This review primarily focuses on the signaling pathways and the therapeutic potential of various adenosine receptor agonists and antagonists across various cancer types, highlighting their ongoing evaluation in preclinical and clinical trials, both as monotherapies and in rational combination with immunotherapy, chemotherapy, or targeted therapies, potentially leading to the development of advanced treatments that could aid in tumor suppression.

Fig. 1. Structure of adenosine.

Fig. 2. Synthesis, storage, release, and signalling pathways of adenosine through adenosine receptors. ATP – “Adenosine triphosphate”, CD73 – “Ecto-5′-nucleotidase” cAMP – “Cyclic adenosine monophosphate”, ADA – “Adenosine deaminase”, ADA – “Adenosine deaminase”, XO – “Xanthine oxidase”, CD39 – Ectonucleoside triphosphate diphosphohydrolase-1, PDE – “Phosphodiesterase”, SAH – “S-adenosyl-homocysteine”, 5-AMP – “5-Adenosine monophosphate”, PNP – “Purine nucleoside phosphorylase”, ADP – “Adenosine diphosphate”, 5NT – “5′-Nucleotidase”, ecto-AK – “Extracellular adenosine kinase”, A₁ AR – “A₁ adenosine receptor”, K⁺ channel – “Potassium channels”, A_2B AR – “A_2B adenosine receptor”, cAMP – “cyclic adenosine monophosphate”, G_i – “inhibitory G-proteins”, A_2A AR – “A_2A adenosine receptor”, AC – “Adenyl cyclase”, G_s – “Stimulatory G-proteins”, PKA – “Protein kinase A” A₃ AR – “A₃ adenosine receptor”. The figure was created in BioRender. Deb, P. (2025).

Fig. 3. A₁ adenosine receptors' role in cancer: molecular signaling pathways. GTP – “Guanosine triphosphate”, PKC – “Protein kinase C”, PKA – “Protein kinase A”, DAG – “Diacylglycerol”, GDP – “Guanosine diphosphate”, ERK1/2 – “Extracellular signal-regulated kinases”, ATP – “Adenosine triphosphate”, PIP2 – “Phosphatidylinositol 4,5-bisphosphate”, and IP3 – “Inositol trisphosphate”, cAMP – “Cyclic adenosine monophosphate” NK – “c-Jun N-terminal kinases”. The figure was created in BioRender. Deb, P. (2025).

Fig. 4. A_2A adenosine receptors' role in cancer: molecular signaling pathways. GTP – “Guanosine triphosphate”, CREB – “cAMP-response element binding protein”, JNK – “c-Jun N-terminal kinases”, ERK1/2 – “Extracellular signal-regulated kinases”, ATP – “Adenosine triphosphate” AKT – “Protein kinase B”, GDP – “Guanosine diphosphate”, and cAMP – “Cyclic adenosine monophosphate”. The figure was created in BioRender. Deb, P. (2025).

Fig. 5. A_2B adenosine receptors' role in cancer: molecular signalling pathways. ATP – “Adenosine triphosphate”, CREB – “cAMP-response element binding protein”, PKC – “Protein kinase C”, IP3 – “Inositol trisphosphate”, GDP – “Guanosine diphosphate”, PLC-β – “phospholipase C-β”, IL-10 – “Interleukin 10”, AKT – “Protein kinase B”, ERK1/2 – “Extracellular signal-regulated kinases”, cAMP – “Cyclic adenosine monophosphate”, FoxP3 – “Forkhead box P3”, DAG – “Diacylglycerol”, PKA-“Protein kinase A”, GTP – “Guanosine trihosphate”, JNK – “c-Jun N-terminal kinases”, PIP2 – “Phosphatidylinositol 4,5-bisphosphate” and TGF-β “Transforming growth factor β”. The figure was created in BioRender. Deb, P. (2025).

Fig. 6. A₃ adenosine receptors' role in cancer: molecular signaling pathways. ERK1/2 – “Extracellular signal-regulated kinases”, ATP – “Adenosine triphosphate”, PKA – “protein kinase A”, PIP2 – “Phosphatidylinositol 4,5-bisphosphate”, FoxP3 – “Forkhead box P3”, GSK-3β – “Glycogen synthase kinase-3β”, IP3 – “Inositol trisphosphate”, cAMP – “Cyclic adenosine monophosphate”, JNK – “c-Jun N-terminal kinases”, DAG “Diacylglycerol”, PKC – “Protein kinase C”, PKB – “Protein kinase B”, RhoA – “Ras homolog family member A” and NFκB – “Nuclear factor kappa-light-chain-enhancer of activated B cells”. The figure was created in BioRender. Deb, P. (2025).

Fig. 7. Impact of structural modifications of adenosine and xanthine derivatives on adenosine receptor binding.

Fig. 8. Potential A₁ adenosine receptor agonists exhibiting promising anticancer properties.

Fig. 9. Potential A₁ adenosine receptor antagonist exhibiting promising anticancer properties.

Fig. 10. Potential A_2A adenosine receptor agonist exhibiting promising anticancer properties.

Fig. 11. Potential A_2A adenosine receptor antagonists exhibiting promising anticancer properties.

Fig. 12. Potential A_2B adenosine receptor antagonists exhibiting promising anticancer properties.

Fig. 13. Potential A₃ adenosine receptor agonists exhibiting promising anticancer properties.

Fig. 14. Potential A₃ adenosine receptor antagonists exhibiting promising anticancer properties.

Prasenjit Maity

Swastika Ganguly

Pran Kishore Deb