Iridium-based electrocatalysts are the most promising candidates for the acidic oxygen evolution reaction (OER). Considering their high cost and scarcity, it is imperative to maximize atom utilization and enhance the intrinsic activity of iridium. In this work, IrOx sub-2 nm clusters are stabilized on TiO2 supports via metal support interaction (MSI) induced by vacancy defects in TiO2. The strength of MSI is readily tuned by the type of vacancies: oxygen vacancies in TiO2 (VO-TiO2) induce the adsorbed MSI with relatively weak strength, while titanium vacancies in TiO2 (VTi-TiO2) lead to the strong embedded MSI. The tunable MSI further modulates the electronic structure of IrOx sub-2 nm clusters. IrOx/VO-TiO2 with adsorbed MSI exhibits an optimized electronic structure with a downshifted d-band center of IrOx, resulting in a reduced binding energy with oxygen and a low energy barrier of the rate-determining step for OER. Consequently, IrOx/VO-TiO2 delivers an activity twice that of commercial IrO2 and a good stability for 120 h in a practical proton exchange membrane water electrolyzer. Our study provides a guideline for the rational design of acidic OER catalysts based on modulating the electronic structure of IrOx sub-2 nm clusters via tunable MSI.