Midkine (MDK) as a central regulator of the tumor microenvironment: From developmental cytokine to therapeutic target

Midkine (MDK) is an oncofetal, heparin-binding cytokine that is re-expressed across diverse cancers and correlates with aggressive disease and treatment resistance. This review synthesizes current evidence on MDK as a coordinator of tumor-intrinsic signaling and microenvironmental remodeling. We summarize MDK structural features, extracellular matrix interactions, and receptor systems that mediate MDK signaling, highlighting LRP1 and PTPRZ1 with context-dependent participation of ALK/LTK, nucleolin and integrins. Downstream, MDK engages MAPK, PI3K-AKT, STAT3 and NF-κB pathways to promote tumor cell survival, epithelial-mesenchymal plasticity, and therapeutic stress tolerance. We then focus on tumor microenvironment (TME) programs shaped by MDK, including angiogenesis, fibroblast activation and extracellular matrix remodeling, and the establishment of immunosuppressive niches. Across tumor types, MDK is linked to impaired dendritic-cell function, polarization of tumor-associated macrophages, accrual of myeloid-derived suppressor cells and reduced CD8 + T-cell cytotoxic fitness. Finally, we review translational opportunities and challenges, including candidate biomarkers (tumor MDK by IHC/RNA and circulating MDK by ELISA) and rational combination strategies that pair MDK blockade with MAPK-pathway inhibitors or PD-1/PD-L1 immunotherapy. Collectively, these data position MDK as a tractable node connecting tumor-intrinsic signaling with stromal and immune regulation. • MDK resurfaces in cancers as an oncofetal cytokine organizing the TME. • MDK signals via LRP1/PTPRZ1 (±ALK/LTK) to drive MAPK-PI3K-STAT and NF-κB. • MDK promotes angiogenesis, fibrosis, and metabolic stress adaptation. • MDK enforces immune suppression via DC dysfunction, M2 macrophages, and MDSCs. • Biomarker-guided MDK blockade may synergize with MEK/SHP2 and PD-1/PD-L1 therapy.