Harnessing reactive oxygen species for precision medicine: ROS-Activatable PROTACs for lung Cancer.

Reactive oxygen species (ROS) play a pivotal role in maintaining cellular balance, functioning both as essential messengers in signaling pathways and as agents of oxidative damage. In cancer their influence is paradoxical: moderate ROS levels can foster tumor growth, whereas excessive accumulation triggers cell death. In lung cancer-the foremost cause of cancer-related deaths globally-disrupted ROS regulation contributes to DNA instability, abnormal pathway activation, and therapeutic resistance. Traditional approaches that manipulate ROS, such as antioxidant treatments, enzyme inhibition, or ROS-enhancing drugs, demonstrated inconsistent results due to the intricate nature of redox biology and the variability among lung tumors. In parallel, proteolysis-targeting chimeras (PROTACs) emerged as innovative tools in precision medicine, designed to selectively eliminate cancer-driving proteins. Yet, their clinical application is hindered by challenges including limited absorption and unintended toxicity. To address these drawbacks, researchers have developed "smart-PROTACs," engineered to activate only under tumor-specific conditions. In this context, a particularly promising design involves ROS-activatable PROTACs, which harness the oxidative environment characteristic of cancer cells to achieve targeted action while minimizing harm to normal tissues. This review integrates current insights into the dual functions of ROS in cancer, examines therapeutic strategies aimed at modulating ROS in lung cancer, and emphasizes the potential of ROS-activatable PROTACs as next-generation treatments for these patients. By combining advances in redox biology, chemical innovation, and personalized oncology, these agents may provide new avenues to destabilize tumor survival mechanisms and overcome drug resistance, representing a significant step toward safer and more effective lung cancer therapies.