Insights from Clinical Trials on A<sub>2A</sub> Adenosine Receptor Antagonists for Cancer Treatment
Pran Kishore Deb, Prasenjit Maity, Biprajit Sarkar, Katharigatta N. Venugopala, Rakesh Kumar Tekade, Sanjay Batra
Abstract
Accumulation of high concentrations of adenosine (ADO) in the tumor microenvironment represents an important immunosuppressive mechanism that promotes cancer progression through A 2A receptor signaling. While initial clinical trials demonstrated modest anticancer effects of monotherapy with A 2A 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/A 2A receptor modulation in bolstering antitumor immune responses, covering the intricate mechanisms of A 2A receptor signaling and ongoing clinical advancements of A 2A receptor antagonists and dual A 2A /A 2B 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.