Precision-Engineered PROTACs: Integrating Physical and Chemical Strategies for Targeted Cancer Therapy

Proteolysis-targeting chimeras (PROTACs) have emerged as a transformative therapeutic strategy for targeted protein degradation, offering substantial potential for treating various diseases by specifically eliminating pathogenic proteins. However, the clinical translation of PROTAC technology faces significant challenges due to limited target selectivity, which may lead to off-target effects and potential toxicity in healthy tissues. Recent advances have focused on developing conditionally activatable PROTAC systems to improve their specificity and safety profile. This review comprehensively examines two primary classes of engineered PROTACs: (i) physically regulated systems, including photo-activatable, radiation, and ultrasound-activatable platforms, and (ii) chemically controlled approaches employing bioorthogonal conjugation strategies. We systematically analyze their molecular mechanisms, current clinical applications in oncology, and existing limitations regarding therapeutic efficacy and safety. The development of these precisely controlled PROTAC platforms promises to significantly enhance the clinical utility of targeted protein degradation technology in modern drug discovery.