Stimuli-activatable PROTAC for precise cancer therapy

Proteolysis-targeting chimeras (PROTACs) leverage their "event-driven" mechanism to target traditionally undruggable proteins inaccessible to conventional small molecule inhibitors, thereby significantly expanding the therapeutic landscape of drug discovery. Furthermore, PROTACs overcome the resistance associated with small molecule inhibitors by achieving complete degradation of target proteins rather than transient functional inhibition. However, their sustained catalytic activity may induce off-target effects and systemic toxicity. To mitigate these limitations, stimuli-responsive PROTAC prodrug systems have emerged as a promising strategy to spatiotemporally control PROTAC activation within tumor microenvironments. PROTAC prodrug systems demonstrate tumor microenvironment-responsive activation through endogenous/exogenous stimuli (e. g., light, enzymes, reactive oxygen species), enabling spatiotemporal control of PROTAC liberation. This precision engineering strategy significantly reduces off-target toxicity while maintaining potent on-target protein degradation efficacy. This review provides a systematic overview of cutting-edge advances in stimuli-activatable PROTAC platforms, critically examines current limitations and challenges in the field, and proposes strategic directions for future development to accelerate the evolution of precision cancer therapeutics.