Rewiring immunity: Midkine's emerging role in cancer immune escape and drug resistance

Immunotherapy has transformed cancer care, yet durable responses remain limited by mechanisms of resistance driven by tumors and their microenvironment. Midkine (MDK), a secreted heparin-binding growth factor, has recently emerged as a regulator of the cancer-immune interface. While MDK has long been recognized for its roles in cell survival, proliferation, and angiogenesis, new evidence highlights its ability to reprogram the tumor microenvironment by recruiting myeloid-derived suppressor cells, impairing T cell activation, and disrupting antigen presentation. MDK further reinforces immune evasion and therapeutic resistance through crosstalk with immune checkpoints, stromal components, and signaling pathways, including STAT3, PI3K/AKT, and the Wnt/β-catenin pathway. Here, we summarize current knowledge of MDK's immunoregulatory functions across various cancer types and propose a conceptual framework that positions MDK as a converging node linking oncogenic signaling with immune escape. We also discuss emerging translational strategies to inhibit MDK to overcome therapy resistance and enhance patient outcomes.