Understanding the immunosuppressive microenvironment of glioblastoma (GBM): mechanistic insights and clinical perspectives Glioblastoma (GBM), the most common and malignant brain tumor, is characterized by an immunosuppressive microenvironment that limits the effectiveness of conventional therapies. Despite standard treatments such as surgery, radiotherapy, and chemotherapy, GBM remains challenging due to its genetic heterogeneity and immunosuppressive nature. Recent research has focused on the role of immune cells and their interactions within the GBM microenvironment, revealing key mechanisms that contribute to immune evasion and tumor progression. Myeloid-derived suppressor cells (MDSCs), glioma-associated macrophages/microglia (GAM), and regulatory T cells (Tregs) play critical roles in creating an immunosuppressive environment. MDSCs, though a minority of CD45+ cells in GBM, are central to immune evasion and tumor progression. Understanding these interactions provides insights into potential therapeutic strategies. This review explores the immune regulatory mechanisms in GBM, existing therapeutic targets, and recent insights into MDSC induction and their contribution to immunosuppression. It also surveys ongoing clinical trials and potential treatment strategies, envisioning a future where targeting MDSCs could reshape the immune landscape of GBM. The integration of immunotherapy with other modalities offers a multi-disciplinary approach to improve GBM prognosis and quality of life. The immune system plays a crucial role in combating GBM, but its dysfunction contributes to the tumor's immunosuppressive environment. GBM's immunosuppressive nature is exacerbated by its "cold" tumor status, characterized by minimal neoantigen expression and immune checkpoint activation. The tumor microenvironment (TME) is highly dynamic and complex, with significant intratumoral heterogeneity. This heterogeneity, combined with the TME's unique characteristics, necessitates combination therapies for effective treatment. The TME includes various immune cells, such as TAMs, MDSCs, and Tregs, which contribute to immunosuppression. The blood-brain barrier (BBB) also plays a role in regulating immune cell infiltration, limiting immune surveillance in GBM. Epigenetic mechanisms are increasingly recognized in GBM, influencing immune responses and tumor progression. Metabolic regulation, including acetylation and palmitoylation, also plays a role in GBM's immunosuppressive environment. The interplay between GBM and immune cells is complex, with various signaling pathways and metabolites contributing to immune evasion. Recent studies highlight the importance of targeting specific immune checkpoints and metabolic pathways in GBM treatment. The transcriptome of GBM reveals significant heterogeneity, with different subtypes exhibiting distinct molecular features. These subtypes are associated with different immunosuppressive microenvironments, emphasizing the need for personalized treatment strategies. The crosstalk between GBM and myeloid lineage cells, such as GAMs, is a critical aspect ofUnderstanding the immunosuppressive microenvironment of glioblastoma (GBM): mechanistic insights and clinical perspectives Glioblastoma (GBM), the most common and malignant brain tumor, is characterized by an immunosuppressive microenvironment that limits the effectiveness of conventional therapies. Despite standard treatments such as surgery, radiotherapy, and chemotherapy, GBM remains challenging due to its genetic heterogeneity and immunosuppressive nature. Recent research has focused on the role of immune cells and their interactions within the GBM microenvironment, revealing key mechanisms that contribute to immune evasion and tumor progression. Myeloid-derived suppressor cells (MDSCs), glioma-associated macrophages/microglia (GAM), and regulatory T cells (Tregs) play critical roles in creating an immunosuppressive environment. MDSCs, though a minority of CD45+ cells in GBM, are central to immune evasion and tumor progression. Understanding these interactions provides insights into potential therapeutic strategies. This review explores the immune regulatory mechanisms in GBM, existing therapeutic targets, and recent insights into MDSC induction and their contribution to immunosuppression. It also surveys ongoing clinical trials and potential treatment strategies, envisioning a future where targeting MDSCs could reshape the immune landscape of GBM. The integration of immunotherapy with other modalities offers a multi-disciplinary approach to improve GBM prognosis and quality of life. The immune system plays a crucial role in combating GBM, but its dysfunction contributes to the tumor's immunosuppressive environment. GBM's immunosuppressive nature is exacerbated by its "cold" tumor status, characterized by minimal neoantigen expression and immune checkpoint activation. The tumor microenvironment (TME) is highly dynamic and complex, with significant intratumoral heterogeneity. This heterogeneity, combined with the TME's unique characteristics, necessitates combination therapies for effective treatment. The TME includes various immune cells, such as TAMs, MDSCs, and Tregs, which contribute to immunosuppression. The blood-brain barrier (BBB) also plays a role in regulating immune cell infiltration, limiting immune surveillance in GBM. Epigenetic mechanisms are increasingly recognized in GBM, influencing immune responses and tumor progression. Metabolic regulation, including acetylation and palmitoylation, also plays a role in GBM's immunosuppressive environment. The interplay between GBM and immune cells is complex, with various signaling pathways and metabolites contributing to immune evasion. Recent studies highlight the importance of targeting specific immune checkpoints and metabolic pathways in GBM treatment. The transcriptome of GBM reveals significant heterogeneity, with different subtypes exhibiting distinct molecular features. These subtypes are associated with different immunosuppressive microenvironments, emphasizing the need for personalized treatment strategies. The crosstalk between GBM and myeloid lineage cells, such as GAMs, is a critical aspect of