Significance Checkpoint inhibitor (CPI) immunotherapies have revolutionized the treatment of a wide array of cancers, but their utility remains limited to a subset of patients with favorable disease phenotypes. We show that the generation of peptide-based nanocomplexes carrying immunostimulatory oligonucleotides dramatically increases the potency of certain of these compounds to stimulate toll-like receptor signaling. The administration of immunostimulatory nanocomplexes carrying CpG oligonucleotides generates antitumor effects and enhances the efficacy of checkpoint inhibitor antibody therapy in mouse models of cancer, and the nanocomplex formulation enables drastic reductions in the dose required to generate therapeutic effects.