Exogenous/endogenous stimuli-responsive antitumor prodrugs advance precision chemotherapy

Precision chemotherapy aims to selectively target cancer cells while sparing healthy cells, thereby addressing a major challenge in traditional chemotherapy, off-target toxicity. Stimuli-responsive antitumor prodrugs leverage exogenous or endogenous triggers for targeted drug activation, which represents a significant advancement in this field. Exogenous stimuli, such as light, ionizing radiation, and ultrasound, usually offer spatiotemporal precision at tumor sites to minimize systemic side effects. Similarly, endogenous stimuli, including hypoxia, acidic pH, the overexpression of specific enzymes, and elevated levels of reactive oxygen species (ROS) and glutathione (GSH), exploit the unique tumor microenvironment to facilitate selective activation. These prodrugs undergo specific chemical or enzymatic reactions in response to their respective triggers, releasing active therapeutic agents at desired sites. This review provides an overall analysis of recent advances in both exogenous and endogenous stimuli-responsive prodrugs, with a focus on their design principles, activation mechanisms, and therapeutic efficacy. By highlighting these emerging strategies, we aim to underscore the potential of stimuli-responsive prodrugs to enhance therapeutic efficacy and safety, paving the way for precision chemotherapy.