Insights from Clinical Trials on A2A Adenosine Receptor Antagonists for Cancer Treatment

Accumulation of high concentrations of adenosine (ADO) in the tumor microenvironment represents an important immunosuppressive mechanism that promotes cancer progression through A2A receptor signaling. While initial clinical trials demonstrated modest anticancer effects of monotherapy with A2A receptor antagonists, combination approaches, particularly with immune checkpoint inhibitors, have shown enhanced potential across multiple cancer types. This review examines the therapeutic potential of ADO/A2A receptor modulation in bolstering antitumor immune responses, covering the intricate mechanisms of A2A receptor signaling and ongoing clinical advancements of A2A receptor antagonists and dual A2A/A2B receptor antagonists. Also, we discuss the pivotal role of rational combination strategies in restoring immunocompetence within the tumor microenvironment, thus offering promising prospects for overcoming immune evasion in cancer therapy.