The A2A adenosine receptor (A2AR) is a critical and nonredundant negative regulator of immune cells that protects normal tissues from inflammatory damage. This study hypothesizes that A2AR also protects cancerous tissues by inhibiting incoming antitumor T lymphocytes. Genetic deletion of A2AR in the host resulted in the rejection of established immunogenic tumors in approximately 60% of A2AR-deficient mice, with no rejection observed in control WT mice. Antagonists, including caffeine, or targeting A2 receptors by siRNA pretreatment of T cells improved the inhibition of tumor growth, destruction of metastases, and prevention of neovascularization by antitumor T cells. The data suggest that the effects of A2AR are T cell autonomous. The inhibition of antitumor T cells via their A2AR in the adenosine-rich tumor microenvironment may explain the paradoxical coexistence of tumors and antitumor immune cells in some cancer patients, known as the "Hellstrom paradox." The study proposes targeting the hypoxia → adenosine → A2AR pathway as a cancer immunotherapy strategy to prevent the inhibition of antitumor T cells in the tumor microenvironment. This strategy may also prevent the premature termination of immune response and improve the vaccine-induced development of antitumor and antiviral T cells. The observations of autoimmunity during melanoma rejection in A2AR-deficient mice suggest that A2AR in T cells is also important in preventing autoimmunity. Thus, although using the hypoxia → adenosine → A2AR pathway inhibitors may improve antitumor immunity, the recruitment of this pathway by selective drugs is expected to attenuate the autoimmune tissue damage.The A2A adenosine receptor (A2AR) is a critical and nonredundant negative regulator of immune cells that protects normal tissues from inflammatory damage. This study hypothesizes that A2AR also protects cancerous tissues by inhibiting incoming antitumor T lymphocytes. Genetic deletion of A2AR in the host resulted in the rejection of established immunogenic tumors in approximately 60% of A2AR-deficient mice, with no rejection observed in control WT mice. Antagonists, including caffeine, or targeting A2 receptors by siRNA pretreatment of T cells improved the inhibition of tumor growth, destruction of metastases, and prevention of neovascularization by antitumor T cells. The data suggest that the effects of A2AR are T cell autonomous. The inhibition of antitumor T cells via their A2AR in the adenosine-rich tumor microenvironment may explain the paradoxical coexistence of tumors and antitumor immune cells in some cancer patients, known as the "Hellstrom paradox." The study proposes targeting the hypoxia → adenosine → A2AR pathway as a cancer immunotherapy strategy to prevent the inhibition of antitumor T cells in the tumor microenvironment. This strategy may also prevent the premature termination of immune response and improve the vaccine-induced development of antitumor and antiviral T cells. The observations of autoimmunity during melanoma rejection in A2AR-deficient mice suggest that A2AR in T cells is also important in preventing autoimmunity. Thus, although using the hypoxia → adenosine → A2AR pathway inhibitors may improve antitumor immunity, the recruitment of this pathway by selective drugs is expected to attenuate the autoimmune tissue damage.