A lack of the T cell-inflamed tumor microenvironment limits the efficacy of immune checkpoint inhibitors (ICIs). Activation of stimulator of interferon genes (STING)-mediated innate immunity has emerged as a novel therapeutic approach in cancer therapy. 2',3'-Cyclic GMP-AMP (cGAMP) is a natural STING agonist; however, cGAMP is subjected to endogenous degradation by ecto-nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1). To improve the ICI response rate, we developed <b>29f</b>, a novel ENPP1 inhibitor with phthalazin-1(2<i>H</i>)-one as the core scaffold. <b>29f</b> inhibited the cGAMP hydrolysis by ENPP1 in vitro (IC₅₀ = 68 nM) and enhanced the STING-mediated type I interferon response in both immune and tumor cells. <b>29f</b> demonstrated excellent metabolic stability and bioavailability (<i>F</i> = 65%). Orally administered <b>29f</b> promoted tumor growth inhibition in a CT26 syngeneic model and increased the anti-PD-L1 response. Furthermore, <b>29f</b>-induced immunological memory prevented the tumor relapse against tumor rechallenge, suggesting the promising therapeutic potential of <b>29f</b>.