The study investigates the role of the A2A adenosine receptor (A2AR) in protecting cancerous tissues from antitumor T cells. The authors hypothesized that A2AR, which is known to regulate immune cells and protect normal tissues from inflammatory damage, might also inhibit antitumor T cells in cancerous environments. They found that genetic deletion of A2AR in mice led to the rejection of established immunogenic tumors in approximately 60% of the A2AR-deficient mice, while no rejection was observed in wild-type (WT) mice. Using antagonists like caffeine and siRNA targeting A2 receptors, the authors improved the inhibition of tumor growth, destruction of metastases, and prevention of neovascularization by antitumor T cells. The results suggest that A2AR's effects are T cell autonomous, and inhibiting A2AR in the adenosine-rich tumor microenvironment may explain the paradoxical coexistence of tumors and antitumor immune cells in some cancer patients. The authors propose targeting the hypoxia-adenosine-A2AR pathway as a potential cancer immunotherapy strategy to enhance antitumor immunity without exacerbating autoimmune tissue damage.The study investigates the role of the A2A adenosine receptor (A2AR) in protecting cancerous tissues from antitumor T cells. The authors hypothesized that A2AR, which is known to regulate immune cells and protect normal tissues from inflammatory damage, might also inhibit antitumor T cells in cancerous environments. They found that genetic deletion of A2AR in mice led to the rejection of established immunogenic tumors in approximately 60% of the A2AR-deficient mice, while no rejection was observed in wild-type (WT) mice. Using antagonists like caffeine and siRNA targeting A2 receptors, the authors improved the inhibition of tumor growth, destruction of metastases, and prevention of neovascularization by antitumor T cells. The results suggest that A2AR's effects are T cell autonomous, and inhibiting A2AR in the adenosine-rich tumor microenvironment may explain the paradoxical coexistence of tumors and antitumor immune cells in some cancer patients. The authors propose targeting the hypoxia-adenosine-A2AR pathway as a potential cancer immunotherapy strategy to enhance antitumor immunity without exacerbating autoimmune tissue damage.