Targeting NOTCH-immune crosstalk in gliomas: from mechanisms to therapeutics

Glioblastoma (GBM) is a highly aggressive and treatment-resistant malignancy characterized by an immunosuppressive tumor microenvironment (TME) that promotes disease progression and poor clinical outcomes. Increasing evidence suggests that NOTCH signaling is a key regulator of GBM progression, governing both tumor cell plasticity and immune evasion. In addition to its roles in development and stem cell maintenance, NOTCH signaling modulates interactions among glioma stem-like cells, immune cells, and stromal components. NOTCH signaling in both tumor and stromal compartments modulates immune cell fate decisions, antigen presentation, and inflammatory cytokine expression. This suggests its potential role as a key modulator of immune crosstalk within the TME of GBM. Moreover, dysregulation of the NOTCH signaling pathway may lead to an immunosuppressive TME, enhance tumor heterogeneity, and restrict responses to conventional therapies. Recent investigations also reveal the epigenetic and non-coding RNA patterns that reinforce aberrant NOTCH activity in GBM. Understanding the multifaceted interactions among NOTCH signaling, oncogenic pathways, and immunomodulatory mechanisms could provide insights into the molecular pathogenesis of GBM progression. Here, we discuss the pleiotropic and context-dependent functions of NOTCH signaling in GBM, with particular emphasis on its implications for tumor-immune interactions and its potential as a therapeutic target to address immune escape and treatment resistance.