近期将MAP4K1鉴定为癌症免疫治疗的靶点。癌细胞内部MAP4K1在胶质母细胞瘤（GBM）发展中的贡献及作用机制尚不清楚。我们发现MAP4K1在人类GBM标本中胶质瘤细胞中高表达。高水平的MAP4K1 mRNA普遍存在于IDH-WT和1p/19q非缺失型胶质瘤，并与患者预后不良相关。沉默MAP4K1抑制GBM细胞增殖和胶质瘤生长。GBM细胞和患者样本的转录组分析显示，MAP4K1调节细胞因子—细胞因子受体相互作用和趋化因子信号通路，包括IL-18R和IL-6R。重要的是，MAP4K1丢失通过抑制PI3K-AKT途径降低了膜结合的IL-18R/IL-6R，而MAP4K1恢复则挽救了这一表型，从而促进GBM细胞增殖。MAP4K1缺陷消除了GBM细胞对IL-18的促增殖反应，提示MAP4K1通过内在的IL-18/IL-18R途径发挥了致癌作用。此外，GBM细胞产生的MAP4K1损害了T细胞迁移并减少了小鼠胶质瘤模型中CD8+ T细胞的浸润。总之，我们的研究结果为GBM细胞内MAP4K1在重塑细胞因子-趋化因子网络中推动肿瘤生长和免疫逃逸的病理意义提供了新的见解。© 2023 Sun et al.

MAP4K1 has been identified as a cancer immunotherapy target. Whether and how cancer cell-intrinsic MAP4K1 contributes to glioblastoma multiforme (GBM) progression remains unclear. We found that MAP4K1 was highly expressed in the glioma cells of human GBM specimens. High levels of MAP4K1 mRNA were prevalent in IDH-WT and 1p/19q non-codeletion gliomas and correlated with poor prognosis of patients. MAP4K1 silencing inhibited GBM cell proliferation and glioma growth. Transcriptome analysis of GBM cells and patient samples showed that MAP4K1 modulated cytokine‒cytokine receptor interactions and chemokine signaling pathway, including IL-18R and IL-6R Importantly, MAP4K1 loss down-regulated membrane-bound IL-18R/IL-6R by inhibiting the PI3K-AKT pathway, whereas MAP4K1 restoration rescued this phenotype and therefore GBM cell proliferation. MAP4K1 deficiency abolished GBM cell pro-proliferation responses to IL-18, suggesting an oncogenic role of MAP4K1 via the intrinsic IL-18/IL-18R pathway. In addition, GBM cell-derived MAP4K1 impaired T-cell migration and reduced CD8+ T-cell infiltration in mouse glioma models. Together, our findings provide novel insight into the pathological significance of GBM cell-intrinsic MAP4K1 in driving tumor growth and immune evasion by remodeling cytokine-chemokine networks.© 2023 Sun et al.