Harnessing delta-like ligand 3: bridging biomarker discovery to next-generation immunotherapies in refractory small cell lung cancer

作者：Kangkang Ji, Lin Guo, Dianbao Zuo, Mingqian Feng, Xin Chen, Zhenggang Zhao, Jing Tang, Guoping Chen · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1592291 · 被引用次数：11 · 研究领域：Lung Cancer Research Studies、Peptidase Inhibition and Analysis、Neuroendocrine Tumor Research Advances

Small cell lung cancer (SCLC), accounting for 10-20% of lung cancers, remains one of the most aggressive neuroendocrine malignancies, with fewer than 7% of patients surviving beyond five years. While the addition of immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy has modestly improved outcomes, long-term benefits are limited to a subset of patients, highlighting the critical need for reliable biomarkers and innovative therapies. Delta-like ligand 3 (DLL3), a Notch signaling regulator overexpressed in 70-80% of SCLC tumors, has emerged as a simultaneous biomarker and therapeutic target. This review aims to synthesize recent advances in DLL3-targeted strategies, bridging biomarker-driven diagnostics to next-generation immunotherapies, while addressing clinical challenges and future directions. The 2024 FDA approval of tarlatamab-a bispecific T-cell engager (BiTE) targeting DLL3 and CD3-marks a pivotal advancement, demonstrating improvement in survival in refractory disease. This review examines three key advances reshaping SCLC management: (1) mechanistic links between DLL3-driven tumorigenesis and PD-L1-mediated immunosuppression, (2) clinical progress in antibody-drug conjugates (ADCs) with next-generation payloads (e.g., FZ-AD005), multispecific BiTEs (e.g., HPN328), and engineered CAR-T/NK cells with enhanced metabolic resilience, and (3) precision strategies combining liquid biopsy for dynamic DLL3 profiling with immuno-PET imaging using [89Zr]Zr-DFO-SC1...