PARP7, a polyadenosine diphosphate-ribose polymerase, has been identified as a negative regulator in type I interferon (IFN) signaling. An overexpression of PARP7 is typically found in a wide range of cancers and can lead to the suppression of type I IFN signaling and innate immune response. Herein, we describe the discovery of compound I-1, a novel PARP7 inhibitor with high inhibitory potency (IC50 = 7.6 nM) and selectivity for PARP7 over other PARPs. Especially, I-1 has excellent pharmacokinetic properties and low toxicity in mice and exhibits significantly stronger in vivo antitumor potency (TGI: 67%) than RBN-2397 (TGI: 30%) without the addition of 1-aminobenzotriazole (a nonselective and irreversible inhibitor of cytochrome P450) in CT26 syngeneic mouse models. Our findings reveal that I-1 mainly acts as an immune activator through PARP7 inhibition in the tumor microenvironment, which highlights the potential advantages of I-1 as a tumor immunotherapeutic agent.