IFI30 reprograms glioblastoma-associated macrophage and induces immune evasion by MAFF/PTGS2 pathway

In recent years, immunotherapy has shown obvious advantages in treating cancers. The close interaction between cancer cells and immune cells in the tumor microenvironment (TME) underlies the progression of glioblastoma multiforme (GBM). However, there are no effective immune-related targets against GBM. Here, in silico analyses and experimental data showed that Interferon Gamma Inducible Protein 30 (IFI30), modulated by histone modifications both H3K4me3 and H3K27ac, was up-regulated in GBM and had a potential role in the antitumor immune responses. In vitro and in vivo experiments further revealed that IFI30 modulated the infiltration of tumor-associated macrophages (TAMs) and reduced the proportion of CD8⁺ T cells. Mechanistically, IFI30 induced PGE2 expression in GBM cells via the MAFF/PTGS2 pathway, and PGE2 bound to macrophage EP2/EP4, activating the downstream ERK1/2 and KLF4/STAT6 pathways, stimulating the infiltration of TAMs. Taken together, we characterized the role and mechanisms of IFI30 in the malignant progression of GBM by regulating TAMs, highlighting that IFI30 may benefit GBM patients as a therapeutic target.