A2AR as a key target for immune microenvironment remodeling in prostate cancer

• A2AR overexpression drives immunosuppression in prostate cancer. • A2AR activation induces CD73, immune checkpoints and T cell exhaustion. • High A2AR level predicts poor prognosis in metastatic prostate cancer. • A2AR blockade synergizes with anti-PD-1 therapy to reverse suppression. • A2AR is a master regulator and promising therapeutic target. This study elucidates the critical role of adenosine A2A receptor (A2AR) signaling in prostate cancer progression through comprehensive molecular characterization and clinical validation, demonstrating that A2AR overexpression in prostate cancer cells drives profound immunosuppression via coordinated upregulation of CD73-mediated adenosine production, subsequent activation of immunosuppressive pathways including ARG1, TGF-β, and IL-10 secretion, and induction of immune checkpoint molecules PD-L1 and Galectin-9, which collectively promote myeloid-derived suppressor cell expansion and CD8 + T cell exhaustion while creating an immunologically privileged tumor microenvironment. Clinical correlation analyses across multiple patient cohorts reveal that elevated A2AR expression serves as a powerful independent predictor of aggressive disease progression and poor clinical outcomes, particularly in metastatic castration-resistant prostate cancer, where it exhibits stronger prognostic value than in other solid tumors. A2AR activation not only helps tumors resist immune checkpoint inhibitors but also blocking A2AR can work well with PD-1/PD-L1 treatments by reversing the immune suppression caused by adenosine and boosting the body's ability to fight tumors. The potential for using these findings in real-world clinical settings is backed by models showing that combining A2AR expression with adenosine pathway activity and immune profiling greatly improves the accuracy of risk assessment compared to standard prognostic markers, while earlier studies show that targeting this pathway could be a viable treatment option. These results collectively position A2AR as a master regulator of prostate cancer immunosuppression and a promising biomarker-guided therapeutic target, particularly for combination immunotherapy approaches in advanced disease settings where current treatment options remain limited.