Pan-cancer multi-omic integration of Trop2 reveals biological determinants and translational implications for ADC therapy

Trop2-directed antibody-drug conjugates (ADCs) show activity across epithelial cancers, yet determinants of target expression in tumors and normal tissues remain poorly defined. We integrated bulk and single-cell transcriptomic profiles from over 20,000 samples across TCGA, GTEx and public atlases to map TACSTD2 expression, regulation and functional correlates in solid malignancies and healthy epithelia. TACSTD2 was restricted to epithelial lineages, enriched in multiple tumors and detectable in selected normal epithelia. Genomic alterations were uncommon, whereas DNA methylation showed a consistent inverse association with expression, indicating dominant epigenetic control. TACSTD2 expression was linked to epithelial programs shaping the tumor microenvironment, including pathways related to barrier integrity and variable immune interactions across tumor types, with potential implications for combination with immune-checkpoint inhibitors. Across histologies, TACSTD2 showed modest and context-dependent co-expression with genes involved in ADC-processing and payload sensitivity. These findings indicate that antigen abundance alone is insufficient to predict ADC efficacy or toxicity across histologies.