The Basis for Targeting the Tumor Macrophage Compartment in Glioblastoma Immunotherapy

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.