MDK, also known as midkine, is a multifunctional secreted protein that can act as a cytokine or growth factor. It regulates multiple signaling pathways and is involved in fundamental cellular processes such as survival, proliferation, and migration [2].

In various cancers, MDK has been found to play significant roles. In endometrial carcinoma, EC cells may confer a malignant phenotype to endothelial cells via the MDK-NCL signal, shaping an immunosuppressive tumor microenvironment (TME) [1]. In hepatocellular carcinoma, MDK is a powerful biomarker for early diagnosis, with higher sensitivity compared to α-fetoprotein (AFP) [2]. In colorectal carcinogenesis, MDK is involved in the immune tolerance shown by regulatory T cells to tumor growth, and its increased level is correlated with poor overall survival in CRC patients [3]. In gallbladder cancer with ErbB pathway mutations, elevated MDK promotes immunosuppressive macrophage differentiation and is correlated with poor overall survival [4]. In clear cell renal cell carcinoma, MDK promotes M2 macrophage polarization, predicting a poor prognosis and a poor immunotherapy response [5]. Additionally, in glioblastoma, MDK overexpression leads to enhanced proliferation, apoptosis inhibition, increased invasion, and temozolomide resistance by promoting cancer stem-like properties [6]. In colorectal cancer, targeting the CDK7-MDK axis can suppress irinotecan resistance [7].

In conclusion, MDK is a crucial factor in multiple biological processes, especially in cancer development and progression. Its roles in shaping the TME, promoting metastasis, and contributing to drug resistance across various cancers highlight its importance as a potential therapeutic target. The studies on MDK using different cancer models have provided valuable insights into its functions and implications in disease conditions.