Molecular Mechanisms of TROP2-Mediated Tumor Malignant Progression and Advances in ADC-Targeted Therapy

Abstract

Trophoblast cell-surface antigen 2, encoded by TACSTD2, is a transmembrane glycoprotein with broad expression in epithelial malignancies and limited, compartmentalized expression in many normal adult tissues. Its tumor-associated distribution, rapid internalization, and functional connection with proliferation, epithelial-mesenchymal transition, stem-like phenotypes, chemoresistance, and survival signaling have made TROP2 both a biological driver and a therapeutic entry point. The clinical development of TROP2-directed antibody-drug conjugates has shifted the field from biomarker description toward target-enabled drug delivery. Sacituzumab govitecan established clinical proof of concept by coupling a TROP2 antibody with SN-38 through a hydrolysable linker, while datopotamab deruxtecan and sacituzumab tirumotecan illustrate newer strategies that refine payload chemistry, linker stability, drug-to-antibody ratio, and toxicity management. This review summarizes the molecular features and expression landscape of TROP2, the mechanisms through which TROP2 supports malignant progression, and the design logic and clinical status of representative TROP2-ADCs. Remaining issues include heterogeneous antigen expression, context-dependent signaling, payload resistance, lineage-specific toxicity, and the absence of standardized predictive assays. These issues frame the next stage of TROP2-targeted therapy.