MIF-mediated reprogramming of myeloid lineage within the glioma tumor microenvironment impacts the efficacy of immune stimulatory gene therapy

Gliomas with mutant isocitrate dehydrogenase 1 (mIDH1) represent a distinct subgroup of brain tumors characterized by unique metabolic and immunological profiles compared to wildtype IDH1 (wtIDH1) gliomas. Despite recent progress, the cellular mechanisms underlying tumor progression and immune modulation in these subtypes remain poorly understood. In this study, we employed single-cell RNA sequencing (scRNA-seq) to characterize the cellular heterogeneity of wtIDH1 and mIDH1 gliomas, with a particular focus on myeloid cell populations. Our analyses revealed a marked reduction of monocyte-derived tumor-associated macrophages (Mo-TAMs) and lower expression of macrophage migration inhibitory factor (MIF) in mIDH1 gliomas, which was attributable to epigenetic reprogramming. Mechanistic studies using MIF and CD74 knockout mice demonstrated that the MIF-CD74 axis plays a crucial role in regulating the glioma immune microenvironment, thereby driving tumor growth and progression. Importantly, the combination of immune-stimulatory gene therapy (HSV1-thymidine kinase/Fms-like tyrosine kinase 3 ligand; TK/Flt3L) with MIF inhibition significantly extended survival in models of wtIDH1 glioma. These findings highlight the therapeutic potential of targeting the MIF-CD74 pathway and underscore the importance of integrating immunomodulatory strategies for the treatment of glioma. HighlightsO_LIMutant IDH1 gliomas exhibit fewer Mo-TAMs and increased Mg-TAMs C_LIO_LIMutant IDH1 gliomas have less MIF expression via epigenetic reprogramming. C_LIO_LIMesenchymal wtIDH1 glioma cells are main source of MIF. C_LIO_LIMIF inhibition plus immune stimulatory gene therapy extends survival wtIDH1 glioma. C_LI