B7-H3 (CD276) as a candidate therapeutic target in medullary thyroid cancer.

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy with limited therapeutic options in advanced disease. While selective RET inhibitors have expanded systemic treatment strategies, disease progression frequently occurs over time. Antibody-drug conjugates (ADCs) have shown efficacy in the treatment of solid tumors but require suitable cell-surface targets, which have not yet been systemically characterized in MTC. This study aimed to identify therapeutically relevant surface antigens in MTC using immunohistochemical profiling. In this retrospective exploratory study, tumor specimens of 41 patients with histologically confirmed MTC were analyzed. Formalin-fixed paraffin-embedded tissues from primary tumors were subjected to immunohistochemical staining for six therapeutically relevant cell-surface antigens. Surface expression was assessed and categorized as strong, weak, or absent. Statistical analyses were conducted using descriptive statistics and Fisher's exact test. The study included 41 patients with MTC, representing different tumor stages and clinicopathological characteristics with lymph node involvement in 45%. B7-H3 showed membranous expression in 91% of the included cases with strong expression in 82%, which was consistent across tumor stages and clinical subgroups. In contrast, no expression was detected for Nectin-4, Trop-2, c-Met, PD-L2, and Claudin 18.2 in any evaluable samples. B7-H3 was identified as the only consistently and strongly expressed surface antigen in a clinically heterogeneous MTC cohort. These findings identify B7-H3 as a potential therapeutic opportunity for advanced MTC and underscore the limited number of targetable surface antigens in this disease.