Functional regulation of midkine (MDK) and its link to cancer.
Midkine (MDK) is a heparin-binding growth factor that is minimally expressed in most adult tissues but markedly upregulated in a wide range of malignancies. Accumulating evidence positions MDK as a multifunctional signaling hub that orchestrates tumor progression through its pleiotropic effects on cancer cells and the tumor microenvironment. MDK engages multiple cell surface receptors, including anaplastic lymphoma kinase, low-density lipoprotein receptor-related protein 1, Notch2, and integrins, thereby activating key downstream pathways such as PI3K/AKT, MAPK/ERK, JAK/STAT, and mTOR. Through these signaling networks, MDK promotes tumor cell proliferation, survival, invasion, angiogenesis, metabolic reprogramming, and resistance to therapy. In parallel, MDK exerts profound immunomodulatory effects by shaping the tumor microenvironment, facilitating the recruitment and polarization of immunosuppressive myeloid cells, impairing effector lymphocyte function, and regulating stromal and neural cell interactions via paracrine signaling mechanisms. Recent single-cell transcriptomic studies further highlight MDK's role in mediating intercellular communication across diverse pathological contexts, underscoring its function beyond tumor-intrinsic signaling. Given its extracellular accessibility, disease-associated overexpression, and central role in multiple oncogenic processes, MDK has emerged as an attractive therapeutic target. This review provides a comprehensive overview of the functional regulation of MDK in cancer, summarizing its molecular signaling pathways, contributions to tumor microenvironment remodeling, and involvement in therapeutic resistance. We also discuss current and emerging strategies for targeting MDK, including small-molecule inhibitors, nucleic acid-based approaches, and combination therapies, and highlight key challenges and future directions for translating MDK-targeted interventions into clinical practice.