Abstract

Macrophage migration inhibitory factor has emerged as a central regulator of tumor progression and immune evasion. Initially identified as an inflammatory cytokine, it is now understood as a multifunctional signaling molecule that integrates hypoxia, metabolic stress, oncogenic activation, and tumor microenvironmental remodeling across diverse malignancies. Through pathways involving cluster of differentiation 74, cluster of differentiation 44, and C-X-C motif chemokine receptor 4, macrophage migration inhibitory factor promotes proliferation, survival, angiogenesis, epithelial-mesenchymal transition, invasion, and metastatic competence. It also shapes the tumor microenvironment by enhancing suppressive myeloid infiltration, macrophage polarization, cluster of differentiation 8-positive T-cell exhaustion, regulatory T-cell accumulation, and impaired antigen presentation. These combined effects position macrophage migration inhibitory factor as an immunometabolic mediator linking chronic inflammation with malignant adaptation and therapeutic resistance. Elevated signaling is associated with poor prognosis and reduced response to chemotherapy, radiotherapy, targeted therapy, and immune checkpoint blockade. Overall, macrophage migration inhibitory factor represents a mechanistically important and translationally relevant target whose clinical value will depend on precise biomarker-guided therapeutic integration.