Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor in adults, with a median survival of approximately 15 months despite therapy. Current standard treatment involves surgical resection followed by radiotherapy and concomitant temozolomide chemotherapy, yet therapeutic resistance and inevitable recurrence remain major challenges (Yang et al., 2020). Unlike many other cancers, GBM has shown limited responsiveness to immunotherapies, such as immune checkpoint inhibitors, underscoring the presence of a profoundly immunosuppressive tumor microenvironment and low immune infiltration (Yang et al., 2020, Sarantopoulos et al., 2024).

The failure of immunotherapeutic strategies in GBM has prompted investigation into the cellular and molecular mechanisms underlying immune evasion. One of the defining features of GBM is its ability to suppress both innate and adaptive immune responses while simultaneously promoting tumor-supportive inflammation (Yang et al., 2020, Sarantopoulos et al., 2024, Alorfi et al., 2024, Alghamri et al., 2021). This duality complicates efforts to stimulate effective antitumor immunity and reflects a high degree of intratumoral heterogeneity, both at the cellular and molecular levels.

Compounding this complexity is the unique anatomical and immunological context of the brain. The presence of the blood–brain barrier, specialized resident immune cells such as microglia, and the restricted trafficking of peripheral lymphocytes contribute to a distinct immune landscape in GBM compared to extracranial tumors. Moreover, recent studies have highlighted the functional plasticity of immune and stromal cells within the tumor microenvironment, revealing that their roles are highly dynamic and context-dependent (Gargini et al., 2020).

In this chapter, we explore how this immunologically cold environment is shaped and sustained by a network of signaling interactions. We focus on the molecular factors that mediate immune suppression and tumor progression in GBM, and discuss how a deeper understanding of these interconnected pathways may inform the development of more effective therapeutic strategies.