Spatiotemporal control of prodrug activation through external stimuli for effective and safe on-site release in solid tumors: From current advances to future perspectives.

Achieving precise control over anticancer drug activity remains a key challenge in prodrug design. Stimuli-responsive systems address this limitation by enabling selective drug release within the tumor microenvironment. Among them, externally activated prodrugs (triggered by light, ionizing radiation, or ultrasound) offer superior spatial and temporal precision, with minimal systemic toxicity. This review critically examines recent advances in design strategies, activation mechanisms, and the translational potential of these systems, including both organic photocages and emerging metal-based platforms [e.g. Pt(IV) and Ru(II) complexes]. Particular attention is given to their integration with next-generation therapeutic modalities such as proteolysis-targeting chimeras (PROTACs) and antibody-drug conjugates (ADCs). Externally triggered prodrug technologies are poised to redefine precision oncology by improving efficacy, safety, and on-demand activation from molecular design to preclinical validation.