Ji Kangkang, Guo Lin, Zuo Dianbao, Feng Mingqian, Chen Xin, Zhao Zhenggang, Tang Jing, Chen Guoping
Department of Clinical Medical Research, Binhai County People's Hospital, Binhai Clinical College, Yangzhou University Medical College, Yancheng, Jiangsu, China.
College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, Hubei, China.
Front Immunol. 2025 May 27;16:1592291. doi: 10.3389/fimmu.2025.1592291. eCollection 2025.
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-SC16. Emerging synergies, such as combining DLL3-targeted BiTEs with ICIs to amplify T-cell infiltration or reprogramming CAR-T mitochondrial metabolism, further underscore the potential of multimodal approaches. Together, these developments signal a transformative era in SCLC treatment, where molecular diagnostics and engineered immunotherapies converge to address unmet clinical needs.
小细胞肺癌（SCLC）占肺癌的10%-20%，仍然是最具侵袭性的神经内分泌恶性肿瘤之一，只有不到7%的患者能存活超过五年。虽然在铂类化疗中添加免疫检查点抑制剂（ICI）已适度改善了治疗效果，但长期益处仅限于一部分患者，这凸显了对可靠生物标志物和创新疗法的迫切需求。Delta样配体3（DLL3）是一种在70%-80%的SCLC肿瘤中过表达的Notch信号调节因子，已成为一种同时具有生物标志物和治疗靶点作用的物质。本综述旨在综合DLL3靶向策略的最新进展，将生物标志物驱动的诊断与下一代免疫疗法联系起来，同时应对临床挑战并展望未来方向。2024年美国食品药品监督管理局（FDA）批准了tarlatamab——一种靶向DLL3和CD3的双特异性T细胞衔接器（BiTE）——标志着一个关键进展，证明其在难治性疾病中提高了生存率。本综述探讨了重塑SCLC治疗格局的三个关键进展：（1）DLL3驱动的肿瘤发生与PD-L1介导的免疫抑制之间的机制联系；（2）具有下一代有效载荷（如FZ-AD005）的抗体药物偶联物（ADC）、多特异性BiTE（如HPN328）以及具有增强代谢适应性的工程化CAR-T/NK细胞的临床进展；（3）将用于动态DLL3分析的液体活检与使用[89Zr]Zr-DFO-SC16的免疫PET成像相结合的精准策略。新兴的协同作用，如将靶向DLL3的BiTE与ICI联合使用以增强T细胞浸润或对CAR-T线粒体代谢进行重编程，进一步强调了多模式方法的潜力。总之，这些进展标志着SCLC治疗进入了一个变革性的时代，分子诊断和工程化免疫疗法相结合以满足未满足的临床需求。
