MIF/CD74/CD44 pathway communicates between macrophages and colorectal Cancer cells and predicts survival of patients

Tumor-associated macrophages (TAMs) are key regulators in the tumor microenvironment and play a pivotal role in colorectal cancer (CRC) progression through complex cell-cell communication. However, the molecular mechanisms governing this interaction remain incompletely elucidated. In this study, we firstly analyzed a scRNA-seq dataset from CRC patients to systematically characterize intercellular signaling between CRC cells and macrophages. The results revealed significantly increased macrophage infiltration in CRC tissues compared to normal controls. Notably, the MIF/CD74/CD44 signaling axis was identified as a dominant pathway mediating crosstalk between these two cell types. Analysis of transcriptomic datasets across four independent CRC cohorts with larger sample of patients confirmed consistent upregulation of macrophage and genes within this pathway in tumor tissues. Importantly, a prognostic signature derived from MIF/CD74/CD44-related genes was significantly associated with overall survival in CRC patients. The in vitro co-culture systems of macrophages and CRC cells demonstrated that M2-polarized macrophages effectively activated this pathway, leading to enhanced CRC cell viability and migration. Furthermore, pharmacological inhibition of MIF markedly attenuated these pro-tumorigenic effects. Collectively, these findings highlight the critical involvement of the MIF/CD74/CD44 signaling axis in CRC-macrophage communication and support its potential as a novel prognostic biomarker and therapeutic target in CRC.