Recent studies and clinical evidence have strongly supported the development of adenosine A receptor (AR) antagonists as novel approaches for cancer immunotherapy. By screening our in-house compound library, a pyridinone hit compound () with weak AR antagonistic activity was identified. Further structure-activity relationship studies revealed a series of pyridinone derivatives with strong potency. Compound stood out with a potent AR antagonistic activity (IC = 29.0 nM), good mouse liver microsomal metabolic stability ( = 86.1 min), and excellent oral bioavailability ( = 86.1%). Of note, effectively enhanced the activation and killing ability of T cells in vitro by down-regulation of immunosuppressive molecules ( and ) and up-regulation of effector molecules (, , and ). Moreover, exhibited excellent in vivo antitumor activity with a tumor growth inhibition (TGI) of 56.0% in the MC38 tumor model via oral administration, demonstrating its potential as a novel AR antagonist candidate for cancer immunotherapy.