Objective:

To summarize the cellular and molecular mechanisms underlying immune suppression in glioblastoma (GBM) and discuss emerging therapeutic strategies aimed at overcoming these barriers.

Approach:

• Overview of GBM: GBM is characterized by a profoundly immunosuppressive tumor microenvironment that limits effective antitumor immunity, including immune exclusion and T-cell dysfunction.
• Mechanisms of Immune Suppression: The review details the roles of tumor-associated macrophages, microglia, myeloid-derived suppressor cells, and other immune cells in establishing a suppressive niche through various mechanisms.
• Key Pathways: Key pathways such as TGF-β/SMAD, IL-10/STAT3, IDO–kynurenine metabolism, and others are discussed for their roles in maintaining immune evasion.
• Emerging Therapeutic Strategies: The article discusses potential strategies including myeloid reprogramming, checkpoint blockade, and metabolic interventions, among others.

Key Findings:

• GBM has a profoundly immunosuppressive microenvironment characterized by immune exclusion and T-cell dysfunction.
• Tumor-associated macrophages and microglia play crucial roles in orchestrating immune suppression.
• Key signaling pathways contribute to the maintenance of immune evasion in GBM.
• Single-agent immunotherapy has rarely achieved durable benefits in GBM due to the complex immune landscape.

Interpretation:

A comprehensive understanding of GBM's immunosuppressive mechanisms is essential for developing effective combination therapies.

Limitations:

• The review does not provide specific clinical trial data to support the discussed therapeutic strategies.
• The complexity of GBM's immune microenvironment may limit the generalizability of proposed interventions.

Conclusion:

Understanding the interconnected barriers in GBM may guide the development of multimodal strategies to enhance therapeutic responses.