Advances in Delta-like Ligand 3-Targeted Diagnosis and Treatment

Neuroendocrine neoplasms (NENs) are rare clinical entities that have long posed significant challenges in diagnosis and treatment due to their high histological heterogeneity, a scarcity of effective therapeutic targets, and consequently, limited treatment options. Delta-like ligand 3 (DLL3), an inhibitory ligand of the Notch signaling pathway, plays a crucial role in neuroendocrine tumors and is highly expressed in malignancies such as small-cell lung cancer and small-cell neuroendocrine prostate cancer. With the continuous advancement of DLL3-targeted technologies in recent years, an increasing number of novel DLL3-targeted agents have emerged, offering diverse antibody and ligand platforms for both ImmunoPET imaging and targeted radionuclide therapy (TRT) in nuclear medicine. Meanwhile, DLL3 ImmunoPET imaging enables noninvasive molecular imaging-based stratification of patients with high DLL3 expression. The two modalities are mutually reinforcing and hold promise for advancing the precision diagnosis and clinical translation of DLL3-targeted strategies in NENs. This review summarizes recent key advancements in DLL3-targeted nuclear medicine and discusses future directions for DLL3 ImmunoPET imaging and TRT.