Macrophage migration inhibitory factor: Exploring physiological roles and comparing health benefits against oncogenic and autoimmune risks (Review).

Abstract

Macrophage migration inhibitory factor (MIF), a multifunctional cytokine that plays a central role in immune regulation and tissue homeostasis, is expressed by nearly all cell types in the body. Beyond its well‑established pro‑inflammatory functions, MIF also exerts protective effects in several physiological processes. MIF enhances immune defense by activating macrophages, promoting cytokine release and supporting efficient antigen presentation. Additionally, MIF contributes to tissue repair, neuroprotection, cardiac function and metabolic regulation, facilitating epithelial healing, maintaining redox balance and modulating insulin secretion. MIF signals through multiple receptors, including CD74, CD44, CXC motif chemokine receptor (CXCR)2, CXCR4 and CXCR7, enabling it to act across a wide range of cell types. This complex signaling network allows MIF to function as both a mediator of homeostasis and a driver of pathology, depending on the biological context. Elevated MIF levels and polymorphisms such as ‑794 CATT5‑8 and ‑173G>C have been associated with increased susceptibility to and the severity of autoimmune disorders (such as systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis), cancer (such as breast, lung and colorectal cancer) and other inflammatory diseases. MIF promotes tumor progression, immune evasion and glucocorticoid resistance, positioning it as a potential biomarker and therapeutic target. Therapeutic strategies targeting MIF, such as small‑molecule inhibitors, receptor antagonists and proteolysis‑targeting chimeras, have shown promise in preclinical studies. However, translating these strategies into clinical therapies requires a deeper understanding of the tissue‑specific functions of MIF and the long‑term consequences of its modulation. Future research should focus on elucidating the mechanisms underlying the dual roles of MIF in health and disease, the impact of genetic variations and the development of targeted interventions that preserve its protective functions while minimizing its pathogenic potential. Such insights will be essential for advancing MIF‑based therapies in precision medicine.