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

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Midkine (MDK) is an oncofetal cytokine re-expressed in various cancers, associated with disease aggressiveness and treatment resistance.
• MDK plays a crucial role in both tumor-intrinsic signaling pathways and the remodeling of the tumor microenvironment (TME).

Purpose of the Study:

• To review current evidence on MDK's function in coordinating tumor signaling and TME remodeling.
• To explore MDK's structural features, receptor interactions, downstream signaling, and impact on the TME.
• To discuss translational opportunities, including biomarkers and combination therapies involving MDK blockade.

Main Methods:

• Literature review synthesizing evidence on MDK structure, function, and signaling pathways.
• Analysis of MDK's role in TME components like angiogenesis, fibroblast activation, and immune cell modulation.
• Examination of potential MDK biomarkers and therapeutic strategies.

Main Results:

• MDK signaling involves receptors like LRP1 and PTPRZ1, activating pathways such as MAPK, PI3K-AKT, STAT3, and NF-κB.
• MDK promotes tumor cell survival, epithelial-mesenchymal plasticity, and resistance to therapy.
• MDK shapes an immunosuppressive TME by impairing dendritic cells, polarizing macrophages, and reducing CD8+ T-cell function.

Conclusions:

• MDK is a key regulator connecting tumor-intrinsic signaling with stromal and immune responses in cancer.
• Targeting MDK, through blockade or combination therapies (e.g., with MAPK inhibitors or PD-1/PD-L1 immunotherapy), presents a promising translational strategy.
• Biomarkers for MDK, including tumor and circulating levels, are being developed for clinical application.