Macrophages in Glioblastoma Development and Therapy: A Double-Edged Sword

Abstract

Glioblastoma (GBM) is one of the leading lethal tumors, featuring aggressive malignancy and poor outcome to current standard temozolomide (TMZ) or radio-based therapy. Developing immunotherapies, especially immune checkpoint inhibitors, have improved patient outcomes in other solid tumors but remain fatigued in GBM patients. Emerging evidence has shown that GBM-associated macrophages (GAMs), comprising brain-resident microglia and bone marrow-derived macrophages, act critically in boosting tumor progression, altering drug resistance, and establishing an immunosuppressive environment. Based on its crucial role, evaluations of the safety and efficacy of GAM-targeted therapy are ongoing, with promising (pre)clinical evidence updated. In this review, we summarized updated literature related to GAM nature, the interplay between GAMs and GBM cells, and GAM-targeted therapeutic strategies.

Keywords: glioblastoma; immunotherapy; macrophage; microglia; targeted therapy.

Figure 1

Ontology and polarization of glioblastoma-associated macrophages. Microglia originate from erythromyeloid progenitors (EMP) in the yolk sac. EMP-derived cells are incorporated into the CNS and take on an amoeboid morphology followed by transitioning toward a ramified state. GBM-associated macrophages are derived from monocytes, which arise from hematopoietic stem cells (HSCs) in bone marrow. In the GBM microenvironment, macrophages and microglia are induced by GBM-derived cytokines (such as CSF-1, IL-4/10/13, and TGF-β) and polarized into GAMs.

Figure 2

Functions of glioblastoma-associated macrophages. GAMs release many cytokines that promote the malignant phenotype of GBM, including tumor malignancy, angiogenesis, and treatment resistance (TMZ chemotherapy, radiation, anti-angiogenesis, and immunotherapy).

Figure 3

GAM-targeted therapy in GBM. Targeting the phagocytosis checkpoint is designed to block phagocytosis pairs, such as CD47/SIRPα and CD24/Siglec-10, to enhance the phagocytosis of tumor cells by macrophages; GAM depletion is aimed at reducing the number of GAMs in the TME. Targeting GAM reprogramming is to repolarize protumoral M2-like GAMs into tumor-suppressive M1-like macrophages; chimeric antigen receptor-macrophage (CAR-M) therapy is an approach using genetically engineered approaches to modify macrophages, which present enhanced phagocytosis, enhanced antigen presentation, and repolarization to M1-like macrophages.