Understanding and enhancing the activity of heterogeneous single-atom catalysts (SACs) are indispensable aspects to use them in industrial applications. Among these, low-temperature CO oxidation is considered as a model reaction for testing a wide-range of oxidation catalysts, and as an essential process for the exhaust aftertreatment in modern combustion engines. This study demonstrates that the activity of heterogeneous Cu/ CeO 2 À TiO 2 SAC catalysts can be fine-tuned by controlling the Ce/Ti ratio in CeO 2 À TiO 2 supports, with the highest catalytic activity achieved for a Ce/Ti molar ratio of 0.18. Based on DRIFT, EEL, and EPR spectroscopies, together with high-resolution electron microscopy and H 2 -TPR measurements, it is inferred that the optimized Ce/Ti ratio correlates with i) highest dispersion of separate CeO 2 particles on TiO 2 surface, ii) more facile reduction of Ce 4 + to Ce 3 + , and iii) enhanced formation of À Cu 2 + À OÀ Ce 4 + À .À Cu + À &À Ce 3 + À redox shuttles, which play a dual role for CO adsorption and O 2 -activation. These results extend the understanding of heterogeneous metal single-atom catalysts and constitute a robust approach for the rational control of their catalytic performance in technically relevant applications.