Boronic acid (or ester) is a well-known temporary masking group for developing anticancer prodrugs responsive to tumoral reactive oxygen species (ROS), but their clinic application is largely hampered by the low activation efficiency. Herein, we report a robust photoactivation approach that can spatiotemporally convert boronic acid-caged iridium(III) complex into bioactive under hypoxic tumor microenvironments. Mechanistic studies show that the phenyl boronic acid moiety in is in equilibrium with phenyl boronate anion that can be photo-oxidized to generate phenyl radical, a highly reactive species that is capable of rapidly capturing O at extremely low concentrations (down to 0.02%). As a result, while could hardly be activated by intrinsic ROS in cancer cells, upon light irradiation, the prodrug is efficiently converted into even in limited O supply, along with direct damage to mitochondrial DNA and potent antitumor activities in hypoxic 2D monolayer cells, 3D tumor spheroids, and mice bearing tumor xenografts. Of note, the photoactivation approach could be extended to intermolecular photocatalytic activation by external photosensitizers with red absorption and to activate prodrugs of clinic compounds, thus offering a general approach for activation of anticancer organoboron prodrugs.