Midkine and pleiotrophin in glioma: From mechanistic insights to therapeutic potential.

Midkine (MK) and pleiotrophin (PTN) are heparin-binding cytokines with growth factor properties that play essential roles in central nervous system development and tissue repair. Through pleiotropic, receptor-mediated signaling, they regulate fundamental cellular processes including survival, proliferation, migration, and stress adaptation. In cancer, these developmental programs are frequently co-opted to support tumor growth, angiogenesis, immune evasion, and microenvironmental remodeling via pathways such as PI3K/AKT, MAPK, and ALK. In gliomas, both MK and PTN are consistently overexpressed, with expression increasing alongside tumor grade in IDH1 wild-type tumors, correlating with poor patient survival. Beyond direct tumor-cell effects, accumulating evidence indicates that MK and PTN shape the glioma microenvironment by promoting macrophage recruitment and polarization, modulating immune signaling, and influencing vascular remodeling. This review synthesizes current knowledge on the molecular and cellular functions of MK and PTN in glioma biology, with particular emphasis on their partially overlapping yet distinct receptor and signaling networks that govern tumor cell survival, metabolic adaptation, and invasion. We outline their potential as therapeutic targets, discuss emerging ligand- and receptor-directed strategies, and identify key gaps that must be addressed to enable effective therapeutic translation, especially in light of the complementary and compensatory functions of these two cytokines.