The cGAS–STING pathway is critical for antitumor immune responses in cancer immunotherapy, while degradation of cGAMP by ENPP1 suppresses this signaling. Here, we report the design and biological evaluation of novel ENPP1 inhibitors containing a benzotriazole core and a sulfonimidamide zinc-binding group. Among them, compound 44a showed potent and selective ENPP1 inhibition (IC₅₀ = 13.1 nM), activated STING signaling in HCT116-Dual™ cells, and induced cytokine release in THP-1 cells. Oral administration of compound 44a demonstrated significant antitumor efficacy in the MC38 syngeneic mouse model without observable toxicity, highlighting its potential as an orally bioavailable ENPP1 inhibitor.