When 'Dirty' Drugs Become Useful: Peptide-Guided Exposure Engineering for the Repurposing of Cancer Drugs.

Drug repurposing in oncology is often framed as a drug-target matching exercise, yet many candidates with plausible biological rationales fail in the clinic. In solid tumors, therapeutic outcomes are constrained not only by pharmacological target relevance but also by limited tumor accessibility, heterogeneous intratumoral exposure, loss of context-dependent activity, and dose-limiting systemic toxicity. This perspective argues that repurposing strategies should treat exposure engineering as a design principle alongside molecular selectivity. Peptides that bind cell- or matrix-associated molecules at the tumor site have the potential to implement spatial, temporal, and subcellular control over where and when a drug engages its pharmacological target, thereby enabling confinement of polypharmacology to tumor contexts. Mechanistic modes of peptide-enabled exposure selectivity (homing, anchoring/retention, conditional activation, penetration enhancement, and subcellular biasing), key failure modes, and translational constraints are discussed, together with an exposure-centric screening workflow to prioritize repurposed agents most amenable to peptide-guided rescue. Emphasizing the combination of exposure control and the addressing-element layer clarifies when and how pharmacologically promiscuous drugs may be repurposed safely and effectively.