Advances in light-controllable PROTACs: Design strategies, therapeutic applications and current challenges

Light-controllable protein degradation-targeting chimeras (Light-controllable PROTACs) have emerged as a novel strategy for spatiotemporal regulation of protein degradation, with significant advances in molecular design and therapeutic applications in recent years. By integrating photo-responsive moieties (e.g., photo-caging groups or photo-switchable modules) into the ternary complex system comprising E3 ligase ligands and target protein ligands, researchers have developed reversible ultraviolet and visible light-responsive systems capable of precise degradation of disease-related proteins. This strategy demonstrates high spatiotemporal resolution and minimal off-target toxicity in vitro, holding promise for disease therapy, especially targeted solid tumor therapy. However, challenges such as limited tissue penetration depth and insufficient metabolic stability remain key barriers to clinical translation. To address these limitations, researchers have begun developing other types of controllable PROTACs that can be activated by alternative stimuli such as hypoxia or X-ray irradiation, thereby helping to overcome the tissue penetration constraints associated with light-controlled systems. Based on recent advances in light-controllable PROTACs, this article systematically summarizes their molecular design principles, applications in cancer therapy, and future challenges, aiming to provide novel insights for the development of next-generation dynamic and programmable degradation therapies.