Divergent Crosstalk Between Microglia and T Cells in Brain Cancers: Implications for Novel Therapeutic Strategies
Abstract
:1. Introduction
2. Comparative Overview of Glioblastoma and Brain Metastases
3. Microglia in Glioblastoma and Brain Metastases
3.1. Molecular Mechanisms of Microglial Involvement in GBM Progression
3.2. Molecular Mechanisms of Microglial Involvement in BM Progression
3.3. Microglial Dynamics in Brain Tumor Microenvironments
4. Crosstalk Between Microglia and T Cells in Glioblastoma
4.1. Mechanisms of Microglia-T Cell Interactions in GBM
4.2. Impact of Microglia-T Cell Interactions on Tumor Progression and Immune Evasion
4.3. Molecular Signaling Pathways
5. Crosstalk Between Microglia and T Cells in Brain Metastasis
6. Therapeutic Implications and Future Directions
7. Conclusions
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Mechanism | Description | References |
---|---|---|
Pro-Inflammatory Mechanisms | Cytokine secretion: TNF-α, IL-1β, IL-6, IL-8, IL-12, and IL-23 inhibit tumor progression. | [42] |
miRNA-125b downregulation: Shifts microglial profile to an anti-tumor state. | [43] | |
Pathways: TLR2, CCR1, and CXCR4-STAT3 axis mediates activation. | [54,55,56,58,59,60,61,62,63] | |
Anti-Inflammatory Mechanisms | Cytokine secretion: TGF-β supports tumor growth and immune evasion. | [46,47] |
Transition to an alternative microglial state promotes angiogenesis, tumor proliferation, and immunosuppressive TME. | [50,51,52,53] | |
Increased CD204+ TAMs in high-grade gliomas. | [48,49] | |
Microglial Plasticity | Microglia display context-dependent functions. Early-stage GBM: Anti-tumor role via pro-inflammatory cytokines and targeting nascent tumor cells. | [42] |
Advanced-stage GBM: Transition to tumor-promoting roles due to anti-inflammatory and homeostatic responses. | [50,51,52,53] | |
Angiogenesis Promotion | Exosome circKIF18A: Drives angiogenesis by targeting FOXC2 pathways. Microglia release growth factors supporting vascularization of the tumor environment. | [44] |
Therapeutic Targeting | CSF-1R inhibition: Suppresses glioma progression and modifies microglial activation. | [55] |
Reprogramming microglia to anti-tumor states by targeting pro-tumor signaling pathways (e.g., CXCR4, STAT3) offers potential therapeutic strategies. | [43,55] |
Mechanism | Description | References |
---|---|---|
Pro-Inflammatory Mechanisms | Microglia produce cytokines, reactive oxygen species, and molecular compounds that promote anti-tumor immune responses. | [73] |
Activation of inflammatory pathways such as NF-κB and STAT3 enhances tumor suppression potential. | [62,77] | |
Anti-Inflammatory Mechanisms | Anti-inflammatory microglia secrete cytokines, tissue remodeling factors, and angiogenic molecules that support tumor growth and metastasis. | [74] |
Tumor-derived signaling pathways (e.g., CXCL12-CXCR4) promote tumor invasion and survival. | [61,75,76] | |
Microglial Plasticity | Microglia exhibit cellular plasticity, transitioning between pro-inflammatory and anti-inflammatory states based on tumor and microenvironmental cues. | [64,65,66,67,68,69] |
BM occurs when cancer cells metastasize to the brain via disrupted blood–brain barrier. | [70,71,72] | |
Epigenetic and RNA Regulation | Epigenetic modifications like DNA methylation and histone acetylation shape microglial phenotypes. MicroRNAs and long non-coding RNAs regulate microglial gene expression in the TME. | [80] |
Therapeutic Targeting | Inducing pro-inflammatory microglia enhances radiotherapy effectiveness and suppresses tumor growth. Blocking MIF/CD74 pathway polarizes microglia to pro-inflammatory states, inhibiting tumor progression post-radiotherapy. | [78] |
PRRs like TLRs detect DAMPs to initiate inflammatory responses. | [79] |
Mechanism | Description | References |
---|---|---|
Antigen Presentation | Microglia present tumor-derived antigens to T cells, influencing their activation status (e.g., CD8+ cytotoxic T cells). | [95,115] |
Cytokine Secretion | Secretion of cytokines like IFN-γ, IL-1, and IL-6 modulates T cell activity and shapes immune responses. | [116,117] |
Chemokine Release | Chemokines such as CCL2 and CXCL10 recruit T cells to the tumor microenvironment. | [95,130] |
Immune Evasion Pathways | Microglia express PD-L1, interacting with PD-1 receptors on T cells to suppress their activity. | [120,121] |
Regulatory T Cell Activation | Microglia activate Tregs, which suppress cytotoxic T cells and enhance immune evasion. | [104,131] |
Metabolic Byproducts | The release of lactate and other byproducts suppresses T cell function, aiding tumor immune evasion. | [122,123] |
Cancer Type | Microglia-T Cell Interaction | Key Mechanisms | Pathways Involved | References |
---|---|---|---|---|
Lung Cancer BM | Microglia express PD-L1, binding to PD-1 on T cells, suppressing activity and promoting tumor progression. | - T cell inhibition via PD-L1 expression. - Promotion of immune evasion. | PD-1/PD-L1 | [133,134] |
Breast Cancer BM | Microglia activate regulatory T cells (Tregs), inhibiting cytotoxic T cells and facilitating immune evasion. | - T cell suppression by Tregs. - Tumor growth and resistance via PI3K/Akt/mTOR pathway. | PI3K/Akt/mTOR | [68,135,151] |
Melanoma BM | Microglia interact with γδ T cells, modulating innate and adaptive immunity. | - Immune cell regulation via JAK/STAT pathway. - Angiogenesis via VEGF secretion. | JAK/STAT | [136,138,153] |
General Mechanism | - Microglia secrete MMPs for invasion. - VEGF promotes angiogenesis. - Immunosuppressive cytokines like TGF-β and IL-10 suppress inflammation. - Chemokines (CCL2, CXCL10) attract immune cells but can aid immunosuppression. - PD-L1 expression inhibits T cells. | - Immune suppression via cytokines. - Tumor microenvironment modulation. - Enhanced survival and growth. | VEGF, TGF-β, IL-10, PD-1/PD-L1, CCL2, CXCL10 | [144,147,150] |
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Yi, M.-H.; Lee, J.; Moon, S.; So, E.; Bang, G.; Moon, K.-S.; Lee, K.-H. Divergent Crosstalk Between Microglia and T Cells in Brain Cancers: Implications for Novel Therapeutic Strategies. Biomedicines 2025, 13, 216. https://doi.org/10.3390/biomedicines13010216
Yi M-H, Lee J, Moon S, So E, Bang G, Moon K-S, Lee K-H. Divergent Crosstalk Between Microglia and T Cells in Brain Cancers: Implications for Novel Therapeutic Strategies. Biomedicines. 2025; 13(1):216. https://doi.org/10.3390/biomedicines13010216
Chicago/Turabian StyleYi, Min-Hee, Jinkyung Lee, Subin Moon, EunA So, Geonhyeok Bang, Kyung-Sub Moon, and Kyung-Hwa Lee. 2025. "Divergent Crosstalk Between Microglia and T Cells in Brain Cancers: Implications for Novel Therapeutic Strategies" Biomedicines 13, no. 1: 216. https://doi.org/10.3390/biomedicines13010216
APA StyleYi, M.-H., Lee, J., Moon, S., So, E., Bang, G., Moon, K.-S., & Lee, K.-H. (2025). Divergent Crosstalk Between Microglia and T Cells in Brain Cancers: Implications for Novel Therapeutic Strategies. Biomedicines, 13(1), 216. https://doi.org/10.3390/biomedicines13010216