DLK1: a novel therapeutic target in cancer

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.