Targeting macrophage migration inhibitory factor as a potential therapeutic strategy in colorectal cancer.

Abstract

Survival rates for patients with late-stage colorectal cancer (CRC) remain low due to limited efficacy of current therapeutic regimens. To overcome these challenges, novel drug targets are urgently needed. Macrophage migration inhibitory factor (MIF), an upstream immunoregulatory cytokine, has emerged as a potential target due to its multifaceted role in cancer pathogenesis. During tumorigenesis, MIF protein levels are often elevated in tumor cells through chaperone-mediated stabilization. Although several in vivo studies have implicated MIF in tumor initiation and progression, its role in sustaining established tumors, particularly when derived from epithelial tumor cells, remained unclear. Using a constitutive Mif knockout mouse model, we previously demonstrated that MIF is required for CRC development. Now, we expanded our experimental CRC model towards a more therapeutic rationale. We hypothesized that epithelial-derived MIF is essential for tumor maintenance and might serve as a possible cancer drug target. Therefore, we depleted epithelial MIF during late-stage CRC tumorigenesis in two genetically-engineered and chemically-induced murine CRC models. Our proof-of-principle study reveals that Mif depletion in epithelial tumor cells attenuates cancer maintenance in both CRC models, coinciding with reduced macrophage recruitment and angiogenesis. Our data highlight the potential utility of targeting MIF in CRC patients for therapeutic benefit.