DLL3 as a potential diagnostic and therapeutic target in neuroendocrine neoplasms: A narrative review

Neuroendocrine neoplasms (NENs) represent a diagnostic and therapeutic challenge, due to their heterogeneity and limited treatment options. Conventional imaging techniques and therapeutic strategies may become unreliable during follow-up, due to the tendency of these neoplasms to dedifferentiate over time. Therefore, novel diagnostic and therapeutic options are required for the management of NEN patients. Delta-like ligand 3 (DLL3), an inhibitory ligand of Notch receptor, has emerged as a potential target for novel diagnostic and therapeutic strategies in NENs, since overexpression of DLL3 has been associated with tumor progression, poor prognosis and dedifferentiation in several NENs. This narrative review examines the current evidence about DLL3, its structure, function and association with tumorigenesis in NENs. Ongoing studies exploring the role of DLL3 as an emerging diagnostic marker are reviewed. Promising therapeutic options, such as antibody-conjugated drugs, CAR-T cells and radioimmunoconjugates, are also discussed. • Neuroendocrine neoplasms (NENs) can dedifferentiate over time, making diagnostic and therapeutic strategies unreliable. • DLL3 is a novel promising biomarker, mostly studied in SCLC but also expressed in other NENs. • Our review explores current evidence about DLL3, focusing on ongoing trials and potential clinical applications in NENs.