Ibudilast Inhibits Brain Metastasis Growth by Targeting MIF-CD74 Signaling in Macrophages

Brain metastases represent a significant clinical challenge in systemic cancer, with current treatments rarely achieving curative outcomes and neurologic morbidity dominating patient quality of life. The brain's unique microenvironment often renders therapies effective at extracranial sites ineffective for intracranial tumor control, highlighting a critical gap in understanding brain-specific disease progression. This research redefines the immune molecule CD74, traditionally an antigen presentation marker, as a key component of a brain-induced, disease-promoting myeloid program, offering a novel therapeutic target.

Researchers investigated the role of CD74+ macrophages in brain metastatic colonization using both mouse models and patient-derived organotypic cultures from various tumor origins. They identified tumor-derived macrophage migration inhibitory factor (MIF) as an activator of these macrophages. The study then evaluated the therapeutic potential of the MIF-CD74 inhibitor, ibudilast, to suppress brain metastatic tumor growth. The primary endpoint was the efficacy of ibudilast in inhibiting tumor progression within these preclinical models.

A distinct CD74+ macrophage population was found to emerge specifically during brain metastatic colonization. These macrophages are activated by tumor-derived MIF, initiating a signaling cascade that drives NF-κB activation. This activation establishes a metabolically sustained prometastatic state, intrinsically linked to oxidative phosphorylation and OMA1-mediated mitochondrial plasticity. This pathway represents a viable therapeutic target, as demonstrated by the efficacy of ibudilast. > Ibudilast effectively suppressed brain metastatic tumor growth in mouse models and showed consistent efficacy across patient-derived organotypic cultures from multiple tumor origins. Furthermore, CD74+ brain macrophages were also observed in other neurologic pathologies, suggesting a shared microenvironmental program across diverse brain disorders.