MIF–CD74 Signaling Defines a Brain-Specific Immune Vulnerability in Metastasis and Neurologic Disease

Brain metastases represent a major clinical challenge in systemic cancer, as current treatments are rarely curative and neurologic morbidity dominates patient outcomes. Increasing evidence suggests that the brain functions as a distinct, partially orthogonal ecosystem in which therapeutic success at extracranial sites fails to translate into effective intracranial tumor control, implicating brain-specific microenvironmental programs in disease progression. In this issue of Cancer Research, Álvaro-Espinosa and colleagues redefine the immune molecule CD74, classically viewed as a marker of antigen presentation, as a key component of a brain-induced, disease-promoting myeloid program. A CD74+ macrophage population emerges specifically during metastatic colonization and is activated by tumor-derived macrophage migration inhibitory factor (MIF). MIF-CD74 signaling drives NF-κB activation and establishes a metabolically sustained prometastatic state linked to oxidative phosphorylation and OMA1-mediated mitochondrial plasticity. Importantly, this pathway represents a viable therapeutic target. The MIF-CD74 inhibitor, ibudilast, suppresses brain metastatic tumor growth in mouse models and shows efficacy across patient-derived organotypic cultures from multiple tumor origins. Extending beyond cancer, CD74+ brain macrophages are also observed in other neurologic pathologies, highlighting shared, pan-disease microenvironmental programs mediated by CD74+ macrophages across diverse brain disorders. See related article by Alvaro-Espinosa et al., p. 3249.