B7H3 (also known as CD276) is a co-stimulator checkpoint protein of the cell surface B7 superfamily. Recently, the function beyond immune regulation of B7H3 has been widely studied. However, the expression preference and the regulation mechanism underlying B7H3 in different subtypes of gliomas is rarely understood. We show here that B7H3 expression is significantly decreased in IDH-mutated gliomas and in cultured IDH1-R132H glioma cells. Accumulation of 2-HG leads to a remarkable downregulation of B7H3 protein and the activity of IDH1-R132H mutant is responsible for B7H3 reduction in glioma cells. Inhibition of autophagy by inhibitors like leupeptin, chloroquine (CQ), and Bafilomycin A1 (Baf-A1) blocks the degradation of B7H3 in glioma cells. In the meantime, the autophagy flux is more active with higher LC3B-II and lower p62 in IDH1-R132H glioma cells than in IDH1-WT cells. Furthermore, sequence alignment analysis reveals potential LC3-interacting region (LIR) motifs “F-V-S/N-I/V” in B7H3. Moreover, B7H3 interacts with p62 and CQ treatment significantly enhances this interaction. Additionally, we find that B7H3 is positively correlated with VEGFA and MMP2 by bioinformatics analysis in gliomas. B7H3 and VEGFA are decreased in IDH-mutated gliomas and further reduced in 2-HGhigh gliomas compared to 2-HGlow glioma sections by IHC staining. Our study demonstrates that B7H3 is preferentially overexpressed in IDH wild-type gliomas and could serve as a potential theranostic target for the precise treatment of glioma patients with wild-type IDH.

TNFAIP8, a cytosolic TNF-α-inducible oncogenic molecule, plays pivotal roles in many types of cancers. However, the effect of TNFAIP8 on glioma remains elusive. In this study, we confirmed that TNFAIP8 promoted glioma viability and motility through alteration of nucleotide metabolism and tricarboxylic acid (TCA) cycle. Firstly, bioinformatic analysis indicated that TNFAIP8 expression elevated along with the WHO grade and predicted adverse prognosis in gliomas. Moreover, TNFAIP8 was enriched in gliomas with progressive genotypes, serving as an efficient indicator for mesenchymal glioma. To determine its function in glioblastoma progression, cell viability, migration and invasion were examined by loss/gain of function experiments. TNFAIP8 promoted glioma proliferation, migration, invasion and transition to mesenchymal phenotype. These findings were further confirmed in vivo. RNA sequencing and liquid chromatography-mass spectrometry (LC-MS) results showed impaired nucleotide metabolism and TCA cycle after TNFAIP8 knockdown, implying that TNFAIP8 enhanced glioblastoma progression via metabolic dysfunction. In summary, this study identified a novel oncogene in glioma with great potential for prognostic prediction and subtype identification. Alterations in metabolic process and transition towards mesenchymal subtype were supposed to be the underlying mechanisms for the oncogenic function of TNFAIP8.