Targeting A3 and A2A adenosine receptors in the fight against cancer

Introduction: There is a vicious cycle of tumor hypoxia, high adenosine levels, immune suppression and cancer growth that involves the use of adenosine receptor ligands in tumors. After several years of research, the candidates emerging as promising new anticancer drugs are A₃ adenosine receptor agonists and A_2A receptor antagonists.

Areas covered: The authors give an updated overview of the field related to A₃ receptor agonists and A_2A receptor antagonists in cancer and propose their perspectives on the status of these compounds in oncology. The rationale for the modulation of adenosine receptors in cancer is addressed, starting from the first in vitro evidence of their efficacy up to the animal and clinical studies.

Expert opinion: A₃ and A_2A receptors are attractive targets in oncologic therapy due to their involvement in cancer progression and immune-resistance. Of relevance, the A₃ subtype is also a tumor marker to be used in a personalized drug treatment program while the A_2A receptor, playing a non-redundant role in immunomodulation, may be blocked in combination with checkpoint inhibitors to improve their efficacy. The future will reveal how successful this approach is in the fight against cancer.