Advancing precision chemotherapy and overcoming resistance mechanisms through sortilin-directed peptide-drug conjugates.

Personalized oncology is hindered by limited tumor selectivity and intracellular delivery of cytotoxics. A receptor-targeted strategy addresses this by conjugating anticancer drugs to peptide ligands that bind selectively to receptors enriched on malignant cells. Sortilin (SORT1; neurotensin receptor-3) is a scavenger receptor overexpressed across multiple aggressive cancers and correlates with tumor grade, making it a clinically attractive entry point for targeted delivery. A peptide conjugation platform using a proprietary SORT1-binding sequence (TH19P01) enabled the creation of peptide-drug conjugates (PDCs) with Docetaxel, Doxorubicin, and Camptothecin, facilitating a vectorization approach to enhance tumor selectivity and drug delivery efficacy. In vitro, these PDCs accumulated intracellularly in a SORT1-dependent manner, overcame chemoresistance linked to P‑glycoprotein efflux and to vasculogenic mimicry, selectively targeted cancer stem cells, and enhanced immune cell infiltration. In vivo, they showed improved tolerability and stronger inhibition of tumor xenografts versus unconjugated drugs. These preclinical data underpin a phase 1 trial of Sudocetaxel Zendusortide (TH1902), which has achieved clinically meaningful, durable disease stabilization. Collectively, the work positions SORT1 as a functional hub in tumor aggressiveness and resistance, and establishes SORT1‑directed PDCs as a new precision oncology class. The platform is scalable across payloads, tumor types, and combination regimens, offering a unified approach to simultaneously tackle drug resistance, cancer stem cell persistence, tumor vascular mimicry, and immune evasion.