Emerging trophoblast cell-surface antigen 2-targeting antibody-drug conjugates in gynecological cancers

Trophoblast cell surface antigen 2 (TROP-2) is a transmembrane glycoprotein involved in intracellular signaling pathways that regulate cancer proliferation, invasion, and survival. TROP-2 is minimally expressed in normal tissues but widely overexpressed in epithelial malignancies, including breast, lung, pancreatic, bladder, and gynecologic cancers. Notably, high levels of TROP-2 RNA and protein expression have been reported in endometrial, ovarian, and cervical cancers, supporting its role in tumor progression and its potential value as a therapeutic target. Recent developments have identified TROP-2 as a promising target for antibody-drug conjugates (ADC)s, particularly in advanced or recurrent gynecologic malignancies where therapeutic resistance remains a major clinical challenge. Although immunotherapy, Poly (ADP-ribose) polymerase (PARP) inhibitors and chemotherapy have shown efficacy in subsets of patients, a significant unmet need persists, especially in those previously treated with platinum-based regimens and immune checkpoint inhibitors. Encouraging preclinical data and early-phase clinical trials have prompted the investigation of several anti-TROP-2 ADCs, including sacituzumab govitecan, datopotamab deruxtecan, and sacituzumab tirumotecan. These agents leverage the selective expression of TROP-2 on tumor cells to deliver cytotoxic payloads, while also demonstrating a bystander effect that extends activity to antigen-negative cells. Their clinical application is currently being explored in gynecologic settings. In this review, we provide an overview of TROP-2’s biological role and its relevance as a prognostic and predictive biomarker in gynecologic cancers. We further summarize the available clinical data on TROP-2-targeting ADCs and discuss future perspectives for integrating these agents into therapeutic strategies aimed at improving outcomes in ovarian, endometrial, and cervical cancers.