Extracellular adenosine is an immunosuppressive metabolite that accumulates at higher levels in the tumor microenvironment (TME) compared to normal tissues. Adenosine signaling, through the activation of A_2A and A_2B adenosine receptors (ARs), suppresses anti-tumor immunity, which leads to a decrease in the therapeutic efficacy of immune checkpoint inhibitors (ICIs). To overcome these limitations, we developed novel dual A_2A/A_2B AR antagonists, YU0133 and YU0395. We evaluated whether those dual antagonists could counteract adenosine-mediated immunosuppressive signaling and enhance anti-tumor immunity in combination with ICIs.In western blot analysis, pre-treatment with the dual antagonists followed by stimulation of 5'-N-Ethylcarboxamidoadenosine (NECA), an adenosine receptor agonist, resulted in a reduction of CREB phosphorylation in T lymphoblast and colorectal cancer cell lines. These results demonstrated that YU compounds effectively inhibit NECA-mediated adenosine signaling activation. Additionally, intracellular cytokine staining demonstrated that YU compounds restored CD8⁺ T cell function by increasing IFN-γ production. Furthermore, cell proliferation assays indicated that the dual antagonists reduced the viability of various cell lines at high micromolar concentrations, suggesting they have limited direct cytotoxic effects. Collectively, these results suggest that A_2A/A_2B AR antagonism by YU compounds may improve anti-tumor immunity by disrupting adenosine signaling.