The evolving landscape of DLL3-directed Therapeutics in small cell lung cancer

Small cell lung cancer (SCLC) remains one of the most lethal thoracic malignancies, characterized by rapid progression, early metastasis, and limited durable responses to conventional therapy. Delta-like ligand 3 (DLL3), a Notch pathway inhibitory ligand aberrantly overexpressed on the surface of approximately 70-85% of SCLC tumor cells but largely absent from normal adult tissue, has emerged as a compelling and therapeutically actionable target. Early efforts to exploit DLL3 through the antibody-drug conjugate (ADC) rovalpituzumab tesirine (Rova-T) yielded important mechanistic insights despite failing to demonstrate survival benefit in phase III trials and have since catalyzed a new generation of more refined DLL3-directed strategies. This review critically examines the evolving portfolio of DLL3-targeted therapies across three principal modalities: T-cell engagers, ADCs, and chimeric antigen receptor T-cell (CAR-T) therapies. In parallel, we examine emerging non-DLL3 therapeutic strategies reshaping the broader SCLC landscape. We additionally discuss the translational science underpinning DLL3 as a biomarker, including the emerging roles of circulating tumor cell-based liquid biopsy and DLL3-directed immunoPET-CT imaging in patient selection and treatment monitoring.