Tumor‐Selective and Chemical Activation Strategies for Nitrogen Mustard Prodrugs

Nitrogen mustards are highly potent DNA-alkylating agents, but their clinical utility is limited by systemic toxicity and poor tumor selectivity. Tumor-selective prodrug strategies have emerged to address these challenges, enabling spatiotemporally controlled activation of otherwise inert precursors. These approaches exploit tumor-specific cues such as hypoxia, acidic pH, elevated reactive oxygen species (ROS), and redox imbalance, to achieve precise payload release. Stimulus-induced bond cleavage or structural transformation liberates the masked nitrogen mustard (NM) in situ, facilitating targeted DNA cross-linking. This review highlights molecular design principles underlying diverse activation strategies, emphasizing scaffold modifications and linker chemistries tailored to cancer-associated triggers. We also discuss integration with advanced delivery platforms, including polymeric carriers and nanoplatforms, to enhance tumor accumulation and therapeutic indices while minimizing off-target toxicity. By consolidating recent advances, this review illustrates how bioorthogonal and tumor-selective activation strategies, including those responsive to hypoxia, ROS, and pH, are redefining the precision oncology potential of NM prodrugs.