Tumor-homing peptides in precision oncology: Mechanisms, design and recent advances.

Mechanisms of systemic administration of cytotoxic and immunomodulatory agents are hindered due to poor intratumoral retention and off-target toxicities. While Antibody-Drug Conjugates (ADCs) have achieved substantial clinical success and validated the paradigm of targeted therapy, their large size (~150 kDa) limits their ability to cross blood vessels and interstitial spaces, especially in the dense, collagen-rich stroma of aggressive solid tumors. As a smaller alternative for drug delivery, Tumor-Homing Peptides (THPs) allow for improved tissue permeability, low immunogenicity and rapid systemic clearance. Here, we examine THPs discovery and development trajectory, from phage display strategies to current deep learning-driven design methodologies. We analyze the structural and functional biology of the predominant internalization pathways like the Neuropilin-1 (NRP-1) dependent C-end Rule (CendR) and the Sortilin (SORT1) scavenger receptor, and their use to promote deep tissue penetration. Finally, we assess the translational landscape of early 2026, including the recent FDA withdrawal of the lipophilic peptide-conjugated melphalan flufenamide (Pepaxto®) and the recent clinical success of the cyclic peptide certepetide for pancreatic adenocarcinoma and the ongoing promising studies with chemically constrained bicyclic peptides.