Microglia and Macrophages in Glioblastoma: Landscapes and Treatment Directions

Microglia and Macrophages in Glioblastoma

Academic Background

Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system, characterized by high invasiveness and lethality. Despite standard treatments such as surgery, chemotherapy, and radiotherapy, the survival rate of patients remains extremely limited, with a median survival of only 12-16 months and a five-year survival rate of just 6.8%. In recent years, immunotherapy has achieved significant success in other solid tumors but has failed to markedly improve survival rates in glioblastoma. This is primarily due to the “immune-cold” nature of the glioblastoma tumor microenvironment (TME), where immune cell infiltration is sparse, and tumor-associated macrophages (TAMs) dominate the TME.

TAMs are mainly composed of brain-resident microglia and bone marrow-derived macrophages (BMDMs). These cells exhibit immunosuppressive and tumor-promoting properties within the TME, thereby inhibiting the efficacy of immunotherapy. Therefore, understanding the origin, functional states, and roles of TAMs in the TME is crucial for developing new therapeutic strategies.

Source of the Paper

This paper was co-authored by Georgios Solomou, Adam M. H. Young, and Harry J. C. J. Bulstrode, affiliated with the Wellcome MRC Cambridge Stem Cell Institute at the University of Cambridge and the Department of Neurosurgery at Addenbrooke’s Hospital in the UK. The paper was published online on May 7, 2024, in the journal Molecular Oncology, with the DOI 10.10021878-0261.13657.

Main Content of the Paper

1. Diversity of TAMs in Glioblastoma

The paper begins by reviewing the diversity of TAMs in glioblastoma. TAMs include brain-resident microglia and bone marrow-derived macrophages, which exhibit different functional states within the TME. Hypoxic and necrotic environments in the tumor core promote the enrichment of immunosuppressive TAMs, while the tumor margins are predominantly occupied by microglia, displaying pro-inflammatory and interferon-related TAM signatures.

2. Functional States of TAMs and Therapeutic Strategies

The paper discusses in detail the functional states of TAMs and their implications for therapeutic strategies. The functional states of TAMs can be finely classified using single-cell RNA sequencing (scRNA-seq) and spatial multi-omics technologies. Studies have shown that the functional states of TAMs dynamically change during tumor progression, and these changes are closely related to immune evasion and treatment resistance. Therefore, modulating the functional states of TAMs may emerge as a new strategy for glioblastoma treatment.

3. Origin and Surface Markers of TAMs

The paper also explores the origin and surface markers of TAMs. Microglia originate from the yolk sac, while peripheral macrophages are derived from the bone marrow. Through single-cell transcriptomic analysis, researchers have found that microglia and peripheral macrophages retain their origin characteristics within the TME and exhibit different functional states in various tumor regions. These findings provide new insights into the classification and treatment of TAMs.

4. Targeted Therapy for TAMs

Finally, the paper discusses targeted therapeutic strategies for TAMs. Current strategies mainly include the depletion and functional reprogramming of TAMs. By inhibiting the recruitment and survival of TAMs or inducing their transition to a pro-inflammatory state, the efficacy of immunotherapy may be enhanced. Additionally, gene-editing technologies are being used to engineer TAMs to express pro-inflammatory cytokines or knock out immunosuppressive genes, thereby enhancing anti-tumor immune responses.

Significance and Value of the Paper

This paper systematically reviews the diversity, functional states, and roles of TAMs in the glioblastoma TME, providing a crucial theoretical foundation for developing new therapeutic strategies. Through single-cell and spatial multi-omics technologies, researchers can more precisely classify the functional states of TAMs and reveal their key roles in tumor progression and treatment resistance. These findings not only contribute to understanding the mechanisms of immune evasion in glioblastoma but also offer new directions for developing targeted therapies against TAMs.

Highlights

  1. Application of Single-Cell and Spatial Multi-Omics Technologies: The paper utilizes single-cell RNA sequencing and spatial multi-omics technologies to finely classify the functional states of TAMs, uncovering their dynamic changes within the TME.
  2. Functional Reprogramming of TAMs: The paper proposes new strategies to enhance the efficacy of immunotherapy by modulating the functional states of TAMs, offering a novel direction for glioblastoma treatment.
  3. Application of Gene-Editing Technologies: The paper explores the potential of using gene-editing technologies to engineer TAMs, enabling them to express pro-inflammatory cytokines or knock out immunosuppressive genes, thereby enhancing anti-tumor immune responses.

Conclusion

This paper systematically reviews the diversity, functional states, and roles of TAMs in glioblastoma, providing a crucial theoretical foundation for developing new therapeutic strategies. Through single-cell and spatial multi-omics technologies, researchers can more precisely classify the functional states of TAMs and reveal their key roles in tumor progression and treatment resistance. These findings not only contribute to understanding the mechanisms of immune evasion in glioblastoma but also offer new directions for developing targeted therapies against TAMs.