Tumor-Associated Macrophages in Glioblastoma: Mechanisms of Tumor Progression and Therapeutic Strategies.

Abstract

Glioblastoma (GBM) is an aggressive brain tumor with a highly immunosuppressive microenvironment that promotes tumor progression and therapy resistance. Tumor-associated macrophages (TAMs), comprising up to 50% of the tumor mass, are recruited via chemokine axes such as CCL2/CCR2, CX3CL1/CX3CR1, and CXCL12/CXCR4 and adopt an M2-like immunosuppressive phenotype, facilitating immune escape and angiogenesis. Key signaling pathways, including CSF1R, STAT3, NF-κB, PI3K/Akt, and HIF-1α, regulate TAM function, making them promising therapeutic targets. Strategies such as TAM depletion, reprogramming, and immune checkpoint blockade (PD-1/PD-L1, and CD47-SIRPα) have shown potential in preclinical models. Emerging approaches, including CAR-macrophage (CAR-M) therapy, nanotechnology-based drug delivery, and exosome-mediated modulation, offer new avenues for intervention. However, clinical translation remains challenging due to GBM's heterogeneity and adaptive resistance mechanisms. Future research should integrate multi-omics profiling and AI-driven drug discovery to refine TAM-targeted therapies and improve patient outcomes. This review provides a comprehensive analysis of TAM-mediated immune regulation in GBM and explores evolving therapeutic strategies aimed at overcoming its treatment barriers.