Efficient delivery of therapeutics to immune cells remains a formidable challenge for cancer immunotherapy. In this work, we demonstrate that an aptamer-driven DNA nanodevice, constructed through linkage of a synthetic immunostimulant (Toll-like receptor 9 agonist: CpG motif) to an aptamer, could significantly enhance the immunostimulatory activity by facilitating the uptake and retention of therapeutics in macrophages. Systemic administration of the DNA nanodevice results in efficient tumor growth inhibition in both breast cancer and melanoma mouse models. Our studies suggest that the DNA nanodevice leads to re-education of tumor-associated macrophages and ultimately to reversing the tumor immune microenvironment. The strategy for aptamer-mediated and vehicle-free delivery of immunostimulatory oligonucleotides provides a potential platform for cancer immunotherapy.