Proteolysis-Targeting Chimeras (PROTACs) represent a transformative therapeutic platform for targeted protein degradation across diverse disease indications. However, their potent catalytic activity in normal tissues raises significant concerns regarding off-target toxicity. Here, we present a novel supramolecular self-assembly platform for the bioorthogonal control of PROTAC prodrug activation, enabling tumor-specific protein degradation with minimized systemic toxicity. By exploiting the overproduction of reactive oxygen species (ROS) in pancreatic cancer cells, the supramolecular self-assembly approach selectively accumulates bioorthogonal reaction triggers within the targeted malignant cells, which subsequently facilitates the spatiotemporally controlled activation of the bioorthogonally caged PROTAC. This tumor-selective activation mechanism demonstrates enhanced degradation efficiency in pancreatic cancer cells compared to normal cells. In vivo studies reveal potent tumor growth inhibition with complete preservation of major organ histology, confirming the therapeutic index enhancement achieved through a controllable activation strategy. This biomimetic activation platform establishes a generalizable framework for safer PROTAC-based therapies by integrating tumor-specific microenvironmental cues with bioorthogonal reaction engineering.