肿瘤细胞治疗研究
英文原题：DLK1: a novel therapeutic target in cancer.
Delta样非经典Notch配体1（DLK1）是一种可切割的跨膜蛋白，其表达受到严格调控，并具有发育阶段特异性。
Delta-like non-canonical Notch ligand 1 (DLK1) 是一种可切割的跨膜蛋白，其表达受到严格调控并具有发育限制性。它在胚胎发生过程中高表达，在控制细胞分化和增殖中发挥关键作用，但在成人组织中基本沉默，主要持续存在于内分泌器官的干细胞和祖细胞区室中。值得注意的是，DLK1 在多种恶性肿瘤中持续重新表达，其中在内分泌和神经内分泌肿瘤中观察到的患病率最高，包括肾上腺皮质癌、嗜铬细胞瘤/副神经节瘤、甲状腺髓样癌和神经母细胞瘤。DLK1 表达与不良临床结局相关，并且越来越多地被认为参与维持去分化的、干细胞样肿瘤表型，这可能促进肿瘤进展和治疗耐药。DLK1 在正常成人组织中的限制性表达，结合其细胞表面定位和在肿瘤生物学中的功能相关性，使其成为一个有吸引力的治疗靶点，尤其是在可靶向选择仍然有限的内分泌恶性肿瘤中。多种 DLK1 导向策略目前正在临床前和早期临床开发中推进，包括去岩藻糖基化单克隆抗体、抗体-药物偶联物、树突状细胞疫苗、CAR-T 细胞疗法和放射免疫治疗。早期阶段研究显示出令人鼓舞的安全性特征和疗效信号，新出现的证据表明，肿瘤特异性因素——如类固醇生成、免疫微环境和药物外排机制——可能影响内分泌癌症的应答。本综述汇总了当前关于DLK1生物学及治疗靶向的证据，重点关注内分泌和神经内分泌恶性肿瘤。我们着重介绍了关键的新机制见解、转化挑战，以及在这些高需求癌症亚型中将DLK1作为精准治疗靶点加以利用的未来机遇。
Delta-like non-canonical Notch ligand 1 (DLK1) is a cleavable transmembrane protein with tightly regulated, developmentally restricted expression. It is highly expressed during embryogenesis, where it plays a key role in controlling cellular differentiation and proliferation, but is largely silenced in adult tissues, persisting mainly within stem and progenitor compartments of endocrine organs. Notably, DLK1 is consistently re-expressed across a broad range of malignancies, with the highest prevalence observed in endocrine and neuroendocrine tumours, including adrenocortical carcinoma, phaeochromocytoma/paraganglioma, medullary thyroid carcinoma, and neuroblastoma. DLK1 expression is associated with adverse clinical outcomes and is increasingly implicated in maintaining a de-differentiated, stem-like tumour phenotype that might contribute to tumour progression and therapeutic resistance. The restricted expression of DLK1 in normal adult tissues, combined with its cell-surface localisation and functional relevance in tumour biology, makes it an attractive therapeutic target, particularly in endocrine malignancies where targetable options remain limited. Multiple DLK1-directed strategies are now advancing through preclinical and early clinical development, including afucosylated monoclonal antibodies, antibody-drug conjugates, dendritic cell vaccines, chimeric antigen receptor T-cell therapies, and radioimmunotherapy. Early-phase studies demonstrate encouraging safety profiles and signals of efficacy, with emerging evidence suggesting that tumour-specific factors - such as steroidogenesis, immune microenvironment, and drug efflux mechanisms - may influence response in endocrine cancers. This review collates current evidence on DLK1 biology and therapeutic targeting, with a focus on endocrine and neuroendocrine malignancies. We highlight key novel mechanistic insights, translational challenges, and future opportunities to exploit DLK1 as a precision therapeutic target in these high-need cancer subtypes.
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