Design of conditional and tumor-activated PROTACs for selective degradation in lung cancer.

Lung cancer remains the leading cause of cancer-related mortality worldwide, with limited therapeutic options for patients harboring drug-resistant or undruggable targets. PROteolysis TArgeting Chimeras (PROTACs) have emerged as a promising strategy to selectively degrade oncogenic drivers; however, their clinical translation is hampered by systemic toxicity, off-target effects, and poor pharmacokinetics. To address these limitations, conditional and tumor-activated PROTACs have been developed, enabling spatiotemporal control of protein degradation within the tumor microenvironment. Recent advances include light-responsive PROTACs, glutathione- and ROS-activated degraders, enzyme-cleavable linkers, and nanocarrier-based prodrugs that enhance tumor selectivity. In lung cancer, these strategies show particular promise against KRAS, EGFR, and SMARCA2/4-driven malignancies, while also offering synergy with immunotherapy and chemotherapy. This review highlights current design principles, emerging applications, and future perspectives for conditional and tumor-activated PROTACs, underscoring their transformative potential in precision oncology.