TROP-2 in solid tumors: From oncogenic driver to therapeutic target with antibody-drug conjugates

Trophoblast cell surface antigen 2 (TROP-2) has emerged as a pivotal oncotherapeutic target, distinguished by frequent overexpression across diverse epithelial malignancies and functions as a master regulator of oncogenic signaling networks. This review provides a systematic delineation of TROP-2's molecular architecture and critically analyzes the mechanisms through which it drives tumor progression-primarily via calcium signaling, the mitogen-activated protein kinase (MAPK) pathway, and the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway-establishing the biological rationale for TROP-2 as an ideal target for antibody-drug conjugate (ADC) development. Clinically, TROP-2-directed ADCs, exemplified by sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd), have demonstrated transformative efficacy across multiple solid tumors including triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and urothelial carcinoma (UC). Their target-specific delivery and potent bystander effect have led to regulatory approvals, reshaping standard-of-care landscapes in these malignancies. We also critically examine multidimensional challenges confronting the field, including acquired resistance mechanisms, toxicity-specific management protocols, and the imperative to advance beyond protein expression toward integrated predictive biomarker frameworks. Building upon this assessment, we outline prospective directions including optimization of rational combination therapies, development of novel ADC platforms, strategic shift to earlier disease stages, and implementation of precision stratification based on multi-omics profiling. This synthesis consolidates current understanding of TROP-2 biology and ADC therapy while furnishing comprehensive guidance for ongoing research and clinical translation, charting the course for the next phase of TROP-2-directed drug development.