Tumor‐Selective and Chemical Activation Strategies for Nitrogen Mustard Prodrugs

ABSTRACT 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.