The functional roles of macrophage migration inhibitory factor in the tumor microenvironment

Macrophage Migration Inhibitory Factor (MIF) is a structurally conserved yet functionally versatile cytokine that possesses enzymatic activity and can trigger downstream signaling through multiple receptors (such as CD74/CD44 and CXCR2/4/7). MIF participates in tumor cell survival, metabolic reprogramming, extracellular matrix remodeling, and treatment resistance. It also shapes the tumor immune microenvironment by regulating innate and adaptive immunity. Recent evidence suggests that the biological effects of MIF are not uniform but are shaped by both molecular states and the local tumor microenvironment. At the molecular level, MIF exists in reduced and oxidized forms, exhibits distinct subcellular localizations, and is associated with different signaling profiles and functional characteristics. Its expression and biological activity are further influenced by organ-specific niches. Although high MIF expression is often associated with invasive disease and a poor prognosis in most studies, its clinical significance can vary significantly depending on the type of tumor, disease stage, subcellular localization, and detection method. Due to this complex heterogeneity, the clinical translation of MIF as a biomarker and therapeutic target faces multiple challenges. This review systematically summarizes the structural basis, regulatory mechanisms, and multifunctional properties of MIF in tumors, with a particular focus on elucidating its functional heterogeneity in different TME contexts. Clarifying the context-dependent functions of MIF will provide a theoretical framework for its clinical application as a stratified biomarker and the development of precise intervention strategies.