The adenosine A2A receptor in triple-negative breast cancer: molecular mechanisms and therapeutic implications

Triple-negative breast cancer (TNBC) has been well-recognized as one of the most aggressive subtypes of breast cancer. TNBC lacks the expression of the estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2), due to which TNBC cannot be treated using traditional therapies available for other subtypes of breast cancer. As a result, TNBC remains heavily dependent on cytotoxic chemotherapy and, more recently, immune-checkpoint inhibitors, although the latter provide durable responses in a limited number of patients. Emerging research has underscored the role of tumor immunometabolism in immune evasion and therapy-refractive behavior. One of the most promising mechanisms involves the extracellular adenosine (eADO) axis created by the action of ectonucleotidases CD39/CD73 and gets transduced by the adenosine A receptor (A R). Because the A R is stimulated by an increase in eADO concentration, the metabolism of the immune cells is shifted from a pro-inflammatory, glycolytic state to a more immunosuppressive, anti-inflammatory, oxidative state. This change in the immune cell metabolism represses T-lymphocyte and natural killer (NK)-cell-dependent cytotoxicity and drives myeloid cells, particularly macrophages, to adopt an M -like protumorigenic phenotype. In TNBC, hypoxia as well as oxidative stress upregulates adenosinergic signaling and, as a result, further propagates immune system dysfunction. This review focuses on the mechanistic roles of the A R, while contextualizing its function within tumor biology. It aims to explain A R regulation across distinct tumor microenvironment (TME) compartments, and a critical analysis of its crosstalk with glycolytic metabolic checkpoints, which include hypoxia-inducible factor 1-alpha (HIF-1α) and AMP-activated protein kinase (AMPK). This provides insight into its potential for therapeutic targeting. [Abstract copyright: © 2026. The Author(s).]