Glioblastoma (GBM), the most aggressive primary brain tumor, remains a formidable therapeutic challenge, with a median survival under 15 months. Despite the current standard of care-comprising maximal safe surgical resection, radiotherapy, and temozolomide chemotherapy-patient outcomes have seen minimal improvement over the past two decades. A key barrier to effective treatment is GBM's robust and multifaceted immunosuppressive network, which critically undermines antitumor immunity. While much of the research has focused on the local immunosuppressive tumor microenvironment, systemic immunosuppression represents an equally important yet often underappreciated obstacle, significantly impairing host immune competence. Effective immunotherapy relies on an intact and functional immune system capable of mounting durable T cell-mediated responses. However, GBM induces profound systemic immune dysfunction, manifested by severe lymphopenia and depletion of effector immune cells, which further limits immune-mediated tumor control. Therefore, a comprehensive understanding of both systemic and local immunosuppressive mechanisms is essential for the rational design of effective immunotherapeutic strategies. In this review, we examine the unique physiological features of the brain, dissect the immunosuppressive landscape of GBM at both local and systemic levels, and highlight recent insights into the underlying mechanisms. We also discuss current immunotherapeutic modalities, and emerging drug delivery strategies aimed at overcoming immunosuppression to improve therapeutic efficacy.

Glioblastoma  /  Systemic immunosuppression  /  Local immunosuppression  /  Tumor microenvironment  /  Immunotherapy  /  Lymphopenia