Peptide-drug conjugates in breast cancer therapy: Emerging targets, translational challenges, and optimization strategies.

Peptide-drug conjugates (PDCs) have emerged as a promising class of targeted therapeutics for breast cancer, offering distinct advantages over antibody-based systems, including improved tumor penetration, lower immunogenicity, and flexible chemical synthesis. In recent years, significant progress has been made in identifying novel peptide ligands targeting overexpressed receptors and tumor-associated microenvironment components, thereby enhancing the specificity and efficacy of drug delivery. This review summarizes the latest advances in PDC design for breast cancer therapy, with a focus on emerging molecular targets, linker strategies, and payload selection. Despite encouraging preclinical outcomes, several challenges hinder the clinical translation of PDCs, including limited in vivo stability, rapid clearance, and suboptimal pharmacokinetics. Strategies to overcome these barriers, such as peptide modification, nanocarrier integration, and rational structural optimization are discussed. Overall, PDCs represent a versatile and evolving platform for precision drug delivery, and continued interdisciplinary efforts are essential to accelerate their translation into clinically effective therapies for breast cancer. SIGNIFICANCE STATEMENT: Peptide-drug conjugates represent a promising targeted modality for breast cancer, with the potential to overcome the limited tumor penetration and heterogeneity associated with antibody-based therapies. This review summarizes breast cancer-specific targets and key design principles, and discusses translational barriers and strategies to improve stability, pharmacokinetics, and therapeutic efficacy.