The Basis for Targeting the Tumor Macrophage Compartment in Glioblastoma Immunotherapy

Abstract

Background: Glioblastoma (GBM) remains the most aggressive primary brain tumor with limited treatment options. The immunosuppressive tumor microenvironment (TME), largely shaped by tumor-associated macrophages (TAMs), represents a significant barrier to effective immunotherapy. Objective: This review aims to explore the role of TAMs within the TME, highlighting the phenotypic plasticity, interactions with tumor cells, and potential therapeutic targets to enhance anti-tumor immunity. Findings: TAMs constitute a substantial portion of the TME, displaying functional plasticity between immunosuppressive and pro-inflammatory phenotypes. Strategies targeting TAMs include depletion, reprogramming, and inhibition of pro-tumor signaling pathways. Preclinical studies show that modifying TAM behavior can shift the TME towards a pro-inflammatory state, enhancing antitumor immune responses. Clinical trials investigating inhibitors of TAM recruitment, polarization, and downstream signaling pathways reveal promising yet limited results, necessitating further research to optimize approaches. Conclusions: Therapeutic strategics targeting TAM plasticity through selective depletion, phenotypic reprogramming, or modulation of downstream immunosuppressive signals represent promising avenues to overcome GBM-associated immunosuppression. Early clinical trials underscore their safety and feasibility, yet achieving meaningful clinical efficacy requires deeper mechanistic understanding and combinatorial approaches integrating macrophage-direct therapies with existing immunotherapeutic modalities.

Keywords: glioblastoma; immunotherapy; macrophage polarization; tumor microenvironment; tumor-associated macrophages.

Figure 1

Polarization Continuum. M0, naïve macrophages are induced by various activating factors to polarize into pro-inflammatory or immunosuppressive phenotypes. Pro-inflammatory macrophages (left) are induced by IFN-γ, GM-CSF, LPS, and TNF-α and release pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, IL-8, IL-12, and IL-23. Immunosuppressive macrophages (right) are activated by PPARγ, STAT6, IL-4, IL-13, TGF-β, and CSF-1 and release anti-inflammatory mediators including arginase 1, IL-4, IL-10, IL-13, TGF-β, VEGF, CCL17, and CCL22. Created in BioRender.

Figure 2

Various therapeutic strategies to prevent TAM trafficking into the TME or selectively deplete from within include CSF-1R inhibition via PLX3397 or BLZ945, CCL2/CCR2 axis disruption via CCX872 or CCR2 knockout, and PI3K pathway inhibition via TG100-115 or CDX LIPO.

Figure 3

Therapeutic targets to reprogram macrophages to a pro-inflammatory phenotype include PD-1/PD-L1 blockade, MALT1 inhibition, Gal-9/Tim-3 blockade, IL-10 suppression, miR-25 extracellular vesicles, ITGB3/STAT3 pathway inhibition, sphingomyelin reduction, PTP4A2 reduction, and TRRAP inhibition. Nanoparticles (mRNA-NPs, CpG-Au-NPs) are also employed to module the TAM immune response.

Figure 4

Therapeutic downstream TAM targets to reverse immunosuppression and shift towards a pro-inflammatory TME. Angiogenesis via integrin αvβ3-TGF-β signaling, GBM pseudopodia formation from CCL8 and ERK1/2 phosphorylation, arginine metabolism, and kynurenine-AhR interaction are potential pathways.