Glioblastoma (GBM) is the most aggressive malignant primary brain tumor characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME). The symbiotic interactions between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAM) in the TME are critical for tumor progression. Here, we identified that IFI35, a transcriptional regulatory factor, plays both cell-intrinsic and cell-extrinsic roles in maintaining GSCs and the immunosuppressive TME. IFI35 induced non-canonical NF-kB signaling through proteasomal processing of p105 to the DNA-binding transcription factor p50, which heterodimerizes with RELB (RELB/p50), and activated cell chemotaxis in a cell-autonomous manner. Further, IFI35 induced recruitment and maintenance of M2-like TAMs in TME in a paracrine manner. Targeting IFI35 effectively suppressed in vivo tumor growth and prolonged survival of orthotopic xenograft-bearing mice. Collectively, these findings reveal the tumor-promoting functions of IFI35 and suggest that targeting IFI35 or its downstream effectors may provide effective approaches to improve GBM treatment.

胶质母细胞瘤（GBM）是最具侵袭性的恶性原发性脑肿瘤，其特征是高度异质性和免疫抑制的肿瘤微环境（TME）。 TME 中胶质母细胞瘤干细胞 (GSC) 和肿瘤相关巨噬细胞 (TAM) 之间的共生相互作用对于肿瘤进展至关重要。在这里，我们发现 IFI35（一种转录调节因子）在维持 GSC 和免疫抑制 TME 方面发挥着细胞内在和细胞外在的作用。 IFI35 通过 p105 蛋白酶体加工成 DNA 结合转录因子 p50（与 RELB (RELB/p50) 异二聚化）诱导非经典 NF-kB 信号传导，并以细胞自主方式激活细胞趋化性。此外，IFI35 以旁分泌方式诱导 TME 中 M2 样 TAM 的募集和维持。靶向 IFI35 可有效抑制体内肿瘤生长并延长原位异种移植小鼠的生存期。总的来说，这些发现揭示了 IFI35 的促肿瘤功能，并表明靶向 IFI35 或其下游效应子可能为改善 GBM 治疗提供有效的方法。