Abstract

Dysregulation of cell death is a hallmark of cancer, and overcoming tumor resistance to apoptosis-inducing therapies remains challenging. Inducing immunogenic cell death (ICD), such as pyroptosis, is promising but currently lacks tools for in vivo monitoring and control. Here, we developed a caspase-3-activated, genetically encoded protein expression system—a programmable synthetic biology platform activated by the key apoptotic protease caspase-3—for apoptosis detection. Configured to express fluorescent or luciferase proteins, it enabled high-resolution live-cell apoptosis imaging and in vivo tumor bioluminescence imaging, and it served as a screening tool for proapoptotic microRNAs. Most importantly, engineering it to express a pyroptosis effector triggered apoptosis-coupled pyroptosis, achieving potent cancer cell killing and enhanced in vivo antitumor efficacy. This versatile platform advances apoptosis detection and its conversion to potent ICD, offering an adaptable approach for cancer theranostics.