Stimuli-activatable protein degraders for targeted cancer therapy: from prodrug design to nanoplatform applications

Disruption of proteostasis represents a critical pathological mechanism driving tumorigenesis and progression. Proteolysis targeting chimera (PROTAC) and molecular glue operating via the ubiquitin-proteasome pathway have created new therapeutic paradigms by enabling precise elimination of disease-associated proteins. These technologies not only overcome the constraints of traditionally “undruggable” targets but also enable sustained modulation through “event-driven” mechanism. Despite these advantages, conventional degraders still face limitations such as off-target effects and suboptimal pharmacokinetic profiles. In response, stimuli-activatable degradation platforms have emerged, integrating smart activatable elements to confer spatiotemporal control over degradation activity within the tumor microenvironment. The combined platform of prodrug and nanodelivery system enhanced degrader solubility, prolonged circulation half-life, and enabled tumor-selective accumulation with controllable release. This strategy improved therapeutic efficacy while reducing systemic toxicity. By enabling coordinated regulation of degradation initiation, localization, and termination, such chemical strategies provided a foundation for developing next-generation intelligent degraders with improved precision and reduced toxicity. This review systematically examined stimuli-activatable molecular designs applied to PROTAC, evaluated their roles in achieving tumor-selective protein degradation, and discussed future directions for clinical translation.