Tumor Microenvironment‐Responsive PROTAC Prodrugs: A Pioneering Strategy for Precision Cancer Therapy

ABSTRACT The tumor microenvironment (TME) represents a highly specialized niche that not only supports malignant progression but also serves as a rich source of therapeutic targets. Characterized by distinctive pathophysiological features, including aberrant enzymatic activity, reductive stress, oxygen deprivation, and oxidative stress, the TME creates a unique biochemical landscape that can be exploited for targeted therapeutic interventions. In recent years, proteolysis‐targeting chimeras (PROTACs) have emerged as a revolutionary therapeutic paradigm in precision oncology, offering unprecedented capabilities for targeted protein degradation through hijacking the ubiquitin‐proteasome system. However, the clinical translation of conventional PROTACs faces significant challenges, particularly their inability to distinguish between malignant and healthy tissues, leading to potential off‐target effects and dose‐limiting toxicities. To address these limitations, a new generation of smart PROTAC prodrugs has been developed, designed to remain pharmacologically inert until selectively activated by TME‐specific stimuli. These innovative prodrug strategies employ various triggering mechanisms, including: (1) enzyme‐cleavable masking groups responsive to tumor‐associated proteases/esterases; (2) GSH‐sensitive disulfide linkages that exploit the reductive intracellular environment; (3) hypoxia‐activated prodrug moieties targeting oxygen‐deprived tumor regions; (4) ROS‐labile functional groups that respond to oxidative stress; and (5) pH‐responsive groups that react to the acidic TME. This comprehensive review systematically examines recent advances in TME‐responsive PROTAC prodrug design, with particular emphasis on structure‐activity relationships, activation kinetics, and therapeutic efficacy. Furthermore, we discuss emerging combination strategies that synergize TME‐responsive PROTACs with other treatment modalities, as well as current challenges and future directions in this rapidly evolving field.