Introduction

Glioblastoma (GBM) and lower-grade gliomas (LGG) are aggressive brain tumors with limited treatment options. Recent research has focused on understanding the complex interplay between glioma cells and the tumor microenvironment (TME), particularly the immune component. This mini-review highlights advancements in immunological profiling and therapeutic targeting strategies in gliomas over the past five years, based on the provided literature. We will focus on single-cell analysis of the glioma microenvironment, the role of macrophages and other immune cells, and novel therapeutic targets and strategies.

Single-Cell Landscape of the Glioma Microenvironment

Significant progress has been made in characterizing the cellular heterogeneity of the glioma TME using single-cell RNA sequencing (scRNA-seq). Bożena Kamińska's group utilized scRNA-seq to reveal the functional heterogeneity of glioma-associated brain macrophages (GAMs) in 2020 and 2021 (Natalia Ochocka et al., 2020, Nature Communications; Natalia Ochocka et al., 2021, Nature Communications). This work highlighted the diverse roles of GAMs, including both pro- and anti-tumorigenic functions. Similarly, Kyuson Yun's research group identified S100A4 as a potential immunotherapy target through single-cell analysis of human glioma and immune cells in 2020, 2021, and 2022 (Nourhan Abdelfattah et al., 2020, Nature Communications; Nourhan Abdelfattah et al., 2021, Nature Communications; Nourhan Abdelfattah et al., 2022, Nature Communications). Jiangfei Wang's group provided a comprehensive single-cell atlas of the immunosuppressive microenvironment in initial and recurrent glioblastoma in 2020 (Weilun Fu et al., 2020, Front. immunol.). These studies collectively demonstrate the power of single-cell technologies in dissecting the complex cellular composition and interactions within the glioma TME, paving the way for more targeted therapeutic interventions. Osama Al-Dalahmah's group further refined this understanding in 2023 by re-convolving the compositional landscape of primary and recurrent glioblastoma, revealing prognostic and targetable tissue states (Osama Al‐Dalahmah et al., 2023, Nature Communications). In 2023, Prajwal Rajappa's group used single-cell RNA sequencing to reveal immunosuppressive myeloid cell diversity during malignant progression in a murine model of glioma (Sakthi Rajendran et al., 2023, Cell Reports).

Macrophages and the Glioma Microenvironment

Macrophages play a crucial role in shaping the glioma TME. Several studies have focused on characterizing the phenotype and function of GAMs. Quan Cheng's and Zhixiong Liu's groups investigated the molecular features of macrophages in the glioma TME in 2020 and 2021 (Hao Zhang et al., 2020, Computational and Structural Biotechnology Journal; Hao Zhang et al., 2021, Computational and Structural Biotechnology Journal). Jing Zhang's group developed an MRI radiomics approach to predict survival and tumor-infiltrating macrophages in gliomas in 2021 (Guanzhang Li et al., 2021, Brain). More recently, Feng Wan's group demonstrated that TGFBI secreted by tumor-associated macrophages promotes glioblastoma stem cell-driven tumor growth via integrin αvβ5-Src-Stat3 signaling in 2022 (Peng Peng et al., 2022, Theranostics). Gang Li's group found that EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3 in 2022 (Ziwen Pan et al., 2022, Molecular Cancer). Xuan Wang's group showed that tumor-associated macrophage-derived exosomal LINC01232 induces immune escape in glioma by decreasing surface MHC-I expression in 2023 (Junjun Li et al., 2023, Advanced Science). Weiping Wang's group demonstrated that tumor-associated monocytes promote mesenchymal transformation through EGFR signaling in glioma in 2023 (Yiyun Chen et al., 2023, Cell Reports Medicine). Quan Cheng's group showed that NDC80/HEC1 promotes macrophage polarization and predicts glioma prognosis via single-cell RNA-seq and in vitro experiment in 2024 (Weijie Ye et al., 2024, CNS Neuroscience & Therapeutics). These findings highlight the importance of targeting macrophages to modulate the glioma TME and improve therapeutic outcomes.

Novel Therapeutic Targets and Strategies

Several studies have explored novel therapeutic targets and strategies for gliomas, focusing on immunotherapy and other approaches. Michael Platten's group developed a vaccine targeting mutant IDH1 in newly diagnosed glioma in 2020 and 2021 (Michael Platten et al., 2020, Nature; Michael Platten et al., 2021, Nature). They also showed that tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas in 2020 and 2021 (Mirco Friedrich et al., 2020, Nature Cancer; Mirco Friedrich et al., 2021, Nature Cancer). G. Yancey Gillespie's group investigated oncolytic HSV-1 G207 immunovirotherapy for pediatric high-grade gliomas in 2021 (Gregory K. Friedman et al., 2021, New England Journal of Medicine). Joerg Lahann's, Pedro R. Löwenstein's, and María G. Castro's groups developed a systemic delivery of an adjuvant CXCR4–CXCL12 signaling inhibitor encapsulated in synthetic protein nanoparticles for glioma immunotherapy in 2022 (Mahmoud S. Alghamri et al., 2022, ACS Nano). Yan Wang's group showed that neutralizing IL-8 potentiates immune checkpoint blockade efficacy for glioma in 2023 (Haofei Liu et al., 2023, Cancer Cell). Peng Zhang's group developed STING agonist-loaded, CD47/PD-L1-targeting nanoparticles that potentiate antitumor immunity and radiotherapy for glioblastoma in 2023 (Peng Zhang et al., 2023, Nature Communications). Magnus Essand's and Anna Dimberg's groups showed that tailoring vascular phenotype through AAV therapy promotes anti-tumor immunity in glioma in 2023 (Mohanraj Ramachandran et al., 2023, Cancer Cell). Evanthia Galanis's group investigated carcinoembryonic antigen-expressing oncolytic measles virus derivative in recurrent glioblastoma in a phase 1 trial in 2024 (Evanthia Galanis et al., 2024, Nature Communications). David M. Ashley's group explored understanding and therapeutically exploiting cGAS/STING signaling in glioblastoma in 2024 (Justin Low et al., 2024, Journal of Clinical Investigation). Dasheng Cai's group showed that targeting MS4A4A is a novel pathway to improve immunotherapy responses in glioblastoma in 2024 (Guangcai Shao et al., 2024, CNS Neuroscience & Therapeutics). These studies highlight the diverse range of therapeutic strategies being explored for gliomas, with a particular emphasis on harnessing the immune system to fight these tumors.

Conclusion

The past five years have witnessed significant advancements in our understanding of the glioma microenvironment and the development of novel therapeutic strategies. Single-cell technologies have revolutionized our ability to characterize the cellular heterogeneity of the TME, while studies on macrophages and other immune cells have revealed potential therapeutic targets. Immunotherapeutic approaches, including vaccines, oncolytic viruses, and targeted nanoparticles, are showing promise in preclinical and clinical studies. Continued research in these areas is crucial for improving the outcomes of patients with gliomas.