Targeting DLL3 in Small Cell Lung Cancer: Therapeutic Strategies and the Emerging Role of Tarlatamab

Historically, cancer treatment has been a continuous research achievement in the pharmaceutical sciences, yet significant challenges remain to be addressed. Among these challenges, high-grade neuroendocrine tumors, particularly malignancies such as small cell lung cancer (SCLC), have confronted persistent issues of recurrent relapse due to their rapid doubling time and high growth fraction. Conventional first-line platinum-based chemotherapy and immune checkpoint inhibitors provide only limited survival extension following initial response, with no distinct therapeutic options available after second-line treatment. These therapeutic limitations are associated with aberrant activation of signaling pathways related to the genetic and functional characteristics of SCLC, with Notch signal suppression and DLL3 overexpression being recognized as major molecular features. DLL3 is an inhibitory Notch ligand highly expressed in SCLC that is rarely expressed in normal tissues and appears selectively in tumor cells, making it an attractive therapeutic target. Recently, various therapeutic strategies targeting DLL3 have been developed, including antibody-drug conjugates, bispecific T cell engagers (BiTEs), and chimeric antigen receptor T cells. This review discusses the pathophysiology of SCLC and the role of DLL3, as well as the development process and clinical utility of DLL3-targeted immunotherapeutic strategies. Furthermore, we examine the latest research trends and developmental potential of BiTE-based immunotherapy centered on Tarlatamab among DLL3-targeted therapies.