Engineering peptide-drug conjugates for targeted cancer therapy: design principle, theranostic imaging, and translational challenges.

Peptide-drug conjugates (PDCs) are emerging as a next-generation class of targeted therapeutics designed to overcome key limitations associated with conventional chemotherapy and antibody-drug conjugates (ADCs). By integrating a tumor-homing peptide, a cleavable or stimuli-responsive linker, and a potent cytotoxic payload, PDCs offer enhanced tumor selectivity while maintaining structural simplicity and synthetic flexibility. Compared to bulky monoclonal antibody-based systems, PDCs possess significantly smaller molecular size, enabling improved tumor penetration, rapid tissue diffusion, and reduced immunogenicity. Recent advances in peptide engineering have facilitated the development of ligands targeting integrins, G protein-coupled receptors, and other tumor-overexpressed biomarkers, promoting receptor-mediated internalization and intracellular drug release. Linker chemistry plays a pivotal role in therapeutic performance, with enzyme-sensitive, redox-responsive, and pH-cleavable linkers enabling site-specific drug activation within the tumor microenvironment. Despite their promise, PDCs face challenges including rapid renal clearance, proteolytic degradation, and limited circulation half-life. Strategies such as cyclization, PEGylation, and albumin-binding modification have been explored to enhance stability and pharmacokinetics. Furthermore, emerging theranostic PDC platforms incorporate imaging moieties or radiolabels, enabling real-time visualization of tumor targeting, biodistribution, and treatment response. Such dual-functional systems facilitate biomarker-guided patient stratification and image-guided precision therapy. This review comprehensively discusses the structural design principles, delivery barriers, pharmacokinetic considerations, applications, imaging advancements, and current clinical landscape of PDCs, highlighting their advantages over ADCs and outlining future directions for precision oncology. Collectively, PDCs represent a promising and versatile platform poised to redefine targeted cytotoxic delivery in cancer therapy.