Midkine as a therapeutic node in NF1-driven neuro‑oncology: Biology, biomarkers, and translational strategies

Neurofibromatosis type 1 (NF1) produces a permissive neuro‑oncologic milieu by disabling neurofibromin's GTPase‑activating control over RAS, thereby exaggerating RAF-MEK-ERK and PI3K-AKT signaling. In the central and peripheral nervous systems, this biochemical re‑wiring intersects with developmental and immune circuits to yield optic pathway glioma (OPG) and malignant peripheral nerve sheath tumor (MPNST), two diseases whose clinical courses are shaped by microenvironmental support as much as tumor‑intrinsic genetics. Midkine (MDK), a secreted heparin‑binding growth factor largely silent in adult physiology, is consistently re‑expressed in malignancy and rises with glioma grade. By engaging receptor complexes centered on LRP1, PTPRZ1, and ALK‑family partners, MDK amplifies ERK, AKT, and STAT signaling and conditions angiogenic and immunosuppressive niches. These properties nominate the MDK axis as both biomarker and therapeutic node in NF1‑altered tumors. This review highlights mechanistic and translational evidence supporting biomarker-guided development of MDK inhibitors. We propose combining MDK blockade with MEK, SHP2, or immune checkpoint inhibitors, using serum MDK and phospho-signaling as pharmacodynamic markers. We emphasize the near‑term opportunity in NF1‑OPG and MPNST while drawing lessons from NF1‑altered tumors outside the nervous system that reinforce combination strategies for neuro‑oncology.