IFI35 regulates non-canonical NF-κB signaling to maintain glioblastoma stem cells and recruit tumor-associated macrophages

Cell Death Differ. 2024 Jun;31(6):738-752. doi: 10.1038/s41418-024-01292-8. Epub 2024 Apr 9.

Abstract

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.

MeSH terms

  • Animals
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Glioblastoma* / genetics
  • Glioblastoma* / metabolism
  • Glioblastoma* / pathology
  • Humans
  • Mice
  • NF-kappa B* / metabolism
  • Neoplastic Stem Cells* / metabolism
  • Neoplastic Stem Cells* / pathology
  • Signal Transduction*
  • Tumor Microenvironment
  • Tumor-Associated Macrophages* / metabolism
  • Tumor-Associated Macrophages* / pathology

Substances

  • NF-kappa B