The Role of Chaf1b in Maintaining Glioma Stem Cell Stemness and Regulating Microglial Polarization

Abstract

Glioblastoma (GBM), the most aggressive tumor in the adult central nervous system, remains a major therapeutic challenge due to its high recurrence and resistance to conventional therapies. Recent evidence underscores the pivotal role of glioma stem cells (GSCs) in driving these malignant features. In this study, using intracranial xenograft models established in 4-week-old male BALB/c nude mice and patient-derived primary GSCs, we uncover a critical function of the chromatin assembly factor subunit Chaf1b in sustaining the stemness of GSCs and modulating the tumor immune microenvironment. We show that Chaf1b is markedly overexpressed in high-grade gliomas and GSC populations. Genetic silencing of Chaf1b led to a significant reduction in GSC self-renewal capacity and tumorigenicity, both in vitro and in intracranial xenograft models. Mechanistically, Chaf1b was found to upregulate IL-33 secretion, thereby promoting microglial M2 polarization and activating the PI3K/AKT signaling pathway—effects that were reversible upon IL-33 neutralization. These findings position Chaf1b as a key mediator of GBM aggressiveness and suggest it as a promising target for disrupting the stem-immune axis in GBM.