Aberrant activation of the PI3K pathway has been intensively targeted for cancer therapeutics for decades, leading to more than 40 PI3K inhibitors advanced into clinical trials. However, it is increasingly noticed that PI3K inhibitors often showed limited efficacy as well as a number of serious on-target adverse effects during the clinical development. In this work, we designed and synthesized a novel photocaged PI3K inhibitor 1, which could be readily activated by UV irradiation to release a highly potent PI3K inhibitor 2. Upon UV irradiation, the photocaged inhibitor 1 demonstrated remarkably enhanced antiproliferative activity against multiple cancer cell lines and significant efficacy in the patient-derived tumor organoid model. Furthermore, 1 also showed favorable anticancer activity in an in vivo zebrafish xenograft model. Taken together, the photocaged PI3K inhibitor 1 represents a promising avenue for novel therapeutics toward precise cancer treatment.