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In this work, a novel series of heterotricyclic DNA-PK inhibitors were rationally designed, synthesized, and assessed for their biological activity. In the DNA-PK biochemical assay, most compounds displayed potent enzymatic activity, with IC50values between 0.11 and 71.5 nM. Among them, SK10exhibited the most potent DNA-PK-inhibitory activity (IC50= 0.11 nM). Studies of the mechanism of action indicated that SK10could lower γH2A.X expression levels and demonstrate optimal synergistic antiproliferative activity against Jurkat cells (IC50= 25 nM) when combined with doxorubicin. Importantly, in CT26 and B16–F10 tumor-bearing mouse models, the combination therapies of SK10with chemotherapeutic drug doxorubicin, a PD-L1 antibody, and SWS1(a potent PD-L1 small-molecule inhibitor) demonstrated superior synergistic anticancer and potential immunomodulatory effects. Furthermore, SK10possessed favorable in vivo pharmacokinetic properties [e.g., oral bioavailability (F) = 31.8%]. Taken together, SK10represents a novel heterotricyclic DNA-PK inhibitor with antitumor immune effects and favorable pharmacokinetics.