Leveraging the Mononuclear Phagocyte System for Advancing Glioma Theranostics: Current Insights and Future Directions

Wenhui Wang , Ruijing Wen , Qianbei Li , Zhen Cai , Zihao Ou , Lei Zheng

Aggregate ›› 2025, Vol. 6 ›› Issue (11) : e70182

PDF
Aggregate ›› 2025, Vol. 6 ›› Issue (11) :e70182 DOI: 10.1002/agt2.70182
REVIEW
Leveraging the Mononuclear Phagocyte System for Advancing Glioma Theranostics: Current Insights and Future Directions
Author information +
History +
PDF

Abstract

Gliomas present a significant challenge in oncology due to their often subtle early symptoms and the insidious nature of their growth, which is compounded by the blood–brain barrier. Recent evidence has highlighted the diagnostic and therapeutic potential of monocytes, macrophages, and microglia in the context of glioma. This review focused on emerging evidence and hypotheses concerning the components and interrelationships within the mononuclear phagocyte system (MPS) in the central nervous system and its role in glioma development and invasion. By summarizing the involvement of the MPS in glioma biology, this paper offers a novel perspective for the integration of liquid biopsy and targeted therapies in oncology.

Keywords

glioma / mononuclear phagocyte system / noninvasive diagnosis / targeted therapy / theranostics

Cite this article

Download citation ▾
Wenhui Wang, Ruijing Wen, Qianbei Li, Zhen Cai, Zihao Ou, Lei Zheng. Leveraging the Mononuclear Phagocyte System for Advancing Glioma Theranostics: Current Insights and Future Directions. Aggregate, 2025, 6(11): e70182 DOI:10.1002/agt2.70182

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

M. Weller, P. Y. Wen, S. M. Chang, et al., “Glioma,” Nature Reviews Disease Primers 10 (2024): 33.

[2]

K. D. Miller, Q. T. Ostrom, C. Kruchko, et al., “Brain and Other central Nervous System Tumor Statistics, 2021,” CA: A Cancer Journal for Clinicians 71 (2021): 381–406.

[3]

D. N. Louis, A. Perry, P. Wesseling, et al., “The 2021 WHO Classification of Tumors of the Central Nervous System: A Summary,” Neuro-Oncology 23 (2021): 1231–1251.

[4]

R. Marcus, “What Is Glioblastoma?,” Jama 329 (2023): 1232–1232.

[5]

T. Li, J. Li, Z. Chen, et al., “Glioma Diagnosis and Therapy: Current Challenges and Nanomaterial-Based Solutions,” Journal of Controlled Release 352 (2022): 338–370.

[6]

L. K. Kan, K. Drummond, M. Hunn, D. Williams, T. J. O'Brien, and M. Monif, “Potential Biomarkers and Challenges in Glioma Diagnosis, Therapy and Prognosis,” BMJ Neurology Open 2 (2020): e000069.

[7]

J. N. Sarkaria, L. S. Hu, I. F. Parney, et al., “Is the Blood–Brain Barrier Really Disrupted in all Glioblastomas? A Critical Assessment of Existing Clinical Data,” Neuro-Oncology 20 (2017): 184–191.

[8]

X. Li, L. Li, K. Zhou, et al., “Glioma Shapes Blood–Brain Barrier Integrity and Remodels the Tumor Microenvironment: Links With Clinical Features and Prognosis,” Journal of Clinical Medicine 11 (2022): 5863.

[9]

D. Liu, X. Dai, L. Ye, et al., “Nanotechnology Meets Glioblastoma Multiforme: Emerging Therapeutic Strategies,” WIREs Nanomedicine and Nanobiotechnology 15 (2023): e1838.

[10]

M. Guilliams, F. Ginhoux, C. Jakubzick, et al., “Dendritic Cells, Monocytes and Macrophages: A Unified Nomenclature Based on Ontogeny,” Nature Reviews Immunology 14 (2014): 571–578.

[11]

D. A. Hume, “The Mononuclear Phagocyte System,” Current Opinion in Immunology 18 (2006): 49–53.

[12]

M. Chaib, J. R. Holt, E. L. Fisher, et al., “Protein Kinase C Delta Regulates Mononuclear Phagocytes and Hinders Response to Immunotherapy in Cancer,” Science Advances 9 (2023): eadd3231.

[13]

S. Lin, X. Yang, X. Yang, et al., “Monocyte Distribution Width as a Promising Biomarker for Differential Diagnosis of Chronic hepatitis, Cirrhosis, and Hepatocellular Carcinoma,” Frontiers in Immunology 15 (2024): 1406671.

[14]

S. Gordon and P. R. Taylor, “Monocyte and Macrophage Heterogeneity,” Nature Reviews Immunology 5 (2005): 953–964.

[15]

B. J. Burkett, D. J. Bartlett, P. W. McGarrah, et al., “A Review of Theranostics: Perspectives on Emerging Approaches and Clinical Advancements,” Radiology: Imaging Cancer 5 (2023): e220157.

[16]

F. Fang, E. Wang, M. Fang, H. Yue, H. Yang, and X. Liu, “Macrophage-Based Pathogenesis and Theranostics of Vulnerable Plaques,” Theranostics 15 (2025): 1570–1588.

[17]

D. A. Hume, K. M. Irvine, and C. Pridans, “The Mononuclear Phagocyte System: The Relationship Between Monocytes and Macrophages,” Trends in Immunology 40 (2019): 98–112.

[18]

R. Sun and H. Jiang, “Border-Associated Macrophages in the central Nervous System,” Journal of Neuroinflammation 21 (2024): 67.

[19]

H.-R. Chen, Y.-Y. Sun, C.-W. Chen, et al., “Fate Mapping via CCR2-CreER Mice Reveals Monocyte-to-Microglia Transition in Development and Neonatal Stroke,” Science Advances 6 (2020): eabb2119.

[20]

B.-R. Choi, K. R. Johnson, D. Maric, and D. B. Mcgavern, “Monocyte-Derived IL-6 Programs Microglia to Rebuild Damaged Brain Vasculature,” Nature Immunology 24 (2023): 1110–1123.

[21]

G. Dunsmore, W. Guo, Z. Li, et al., “Timing and Location Dictate Monocyte Fate and Their Transition to Tumor-Associated Macrophages,” Science Immunology 9 (2024): eadk3981.

[22]

W. B. L. Van Den Bossche, A. J. P. E. Vincent, C. Teodosio, et al., “Monocytes Carrying GFAP Detect Glioma, Brain Metastasis and Ischaemic Stroke, and Predict Glioblastoma Survival,” Brain Communications 3 (2021): fcaa215.

[23]

M. Shibutani, K. Maeda, H. Nagahara, et al., “The Peripheral Monocyte Count Is Associated With the Density of Tumor-Associated Macrophages in the Tumor Microenvironment of Colorectal Cancer: A Retrospective Study,” BMC Cancer 17 (2017): 404.

[24]

Y.-L. Tan, Y. Yuan, and L. Tian, “Microglial Regional Heterogeneity and its Role in the Brain,” Molecular Psychiatry 25 (2020): 351–367.

[25]

C. Pallarés-Moratalla and G. Bergers, “The Ins and Outs of Microglial Cells in Brain Health and Disease,” Frontiers in Immunology 15 (2024): 1305087.

[26]

L. J. M. Mastenbroek, S. M. Kooistra, B. J. L. Eggen, and J. R. Prins, “The Role of Microglia in Early Neurodevelopment and the Effects of Maternal Immune Activation,” Seminars in Immunopathology 46 (2024): 1.

[27]

L. C. Mehl, A. V. Manjally, O. Bouadi, E. M. Gibson, and T. L. Tay, “Microglia in Brain Development and Regeneration,” Development 149 (2022): dev200425.

[28]

T. R. F. Green and R. K. Rowe, “Quantifying Microglial Morphology: An Insight Into Function,” Clinical and Experimental Immunology 216 (2024): 221–229.

[29]

X. Wu, J. A. Miller, B. T. K. Lee, Y. Wang, and C. Ruedl, “Reducing Microglial Lipid Load Enhances β Amyloid Phagocytosis in an Alzheimer's Disease Mouse Model,” Science Advances 11 (2025): eadq6038.

[30]

S. C. Woodburn, J. L. Bollinger, and E. S. Wohleb, “The Semantics of Microglia Activation: Neuroinflammation, Homeostasis, and Stress,” Journal of Neuroinflammation 18 (2021): 258.

[31]

A. Deczkowska, I. Amit, and M. Schwartz, “Microglial Immune Checkpoint Mechanisms,” Nature Neuroscience 21 (2018): 779–786.

[32]

M. Colonna and O. Butovsky, “Microglia Function in the Central Nervous System During Health and Neurodegeneration,” Annual Review of Immunology 35 (2017): 441–468.

[33]

C. Gao, J. Jiang, Y. Tan, and S. Chen, “Microglia in Neurodegenerative Diseases: Mechanism and Potential Therapeutic Targets,” Signal Transduction and Targeted Therapy 8 (2023): 359.

[34]

H. Scheiblich, F. Eikens, L. Wischhof, et al., “Microglia Rescue Neurons From Aggregate-Induced Neuronal Dysfunction and Death Through Tunneling Nanotubes,” Neuron 112 (2024): 3106–3125.e8.

[35]

S. G. Utz and M. Greter, “Checking Macrophages at the Border,” Nature Neuroscience 22 (2019): 848–850.

[36]

F. Zheng, T. Dong, Y. Chen, L. Wang, and G. Peng, “Border-Associated Macrophages: From Physiology to Therapeutic Targets in Alzheimer's Disease,” Experimental Neurology 383 (2025): 115021.

[37]

L. Wang, J. Zheng, S. Zhao, et al., “CCR2+ monocytes Replenish Border-Associated Macrophages in the Diseased Mouse Brain,” Cell Reports 43 (2024): 114120.

[38]

A. Silvin, J. Qian, and F. Ginhoux, “Brain Macrophage Development, Diversity and Dysregulation in Health and Disease,” Cellular & Molecular Immunology 20 (2023): 1277–1289.

[39]

J. Zhao, R. Zeng, X. Li, et al., “Dura Immunity Configures Leptomeningeal Metastasis Immunosuppression for Cerebrospinal Fluid Barrier Invasion,” Nature Cancer 5 (2024): 1940–1961.

[40]

M. Bijnen, S. Sridhar, A. Keller, and M. Greter, “Brain Macrophages in Vascular Health and Dysfunction,” Trends in Immunology 46 (2025): 46–60.

[41]

A. Anfray, S. Schaeffer, Y. Hattori, et al., “A Cell-Autonomous Role for Border-Associated Macrophages in ApoE4 Neurovascular Dysfunction and Susceptibility to White Matter Injury,” Nature Neuroscience 27 (2024): 2138–2151.

[42]

P. Aretz, D. Maciaczyk, S. Yusuf, et al., “Crosstalk Between β-Catenin and CCL2 Drives Migration of Monocytes Towards Glioblastoma Cells,” International Journal of Molecular Sciences 23 (2022): 4562.

[43]

M. K. Kranjc, M. Novak, R. G. Pestell, and T. T. Lah, “Cytokine CCL5 and Receptor CCR5 Axis in Glioblastoma Multiforme,” Radiology and Oncology 53 (2019): 397–406.

[44]

Y. Song, Y. Zhang, Z. Wang, et al., “CCL2 Mediated IKZF1 Expression Promotes M2 Polarization of Glioma-Associated Macrophages Through CD84-SHP2 Pathway,” Oncogene 43 (2024): 2737–2749.

[45]

N. Geribaldi-Doldán, C. Fernández-Ponce, R. N. Quiroz, et al., “The Role of Microglia in Glioblastoma,” Frontiers in Oncology 10 (2020): 603495.

[46]

J. Wang, S. Li, Y. Lan, X. Liu, and W. Li, “Glioma-Associated Macrophages: Unraveling Their Dual Role in the Microenvironment and Therapeutic Implications,” Current Medicine 3 (2024): 4.

[47]

D. Matias, J. Balça-Silva, G. C. Da Graça, et al., “Microglia/Astrocytes–Glioblastoma Crosstalk: Crucial Molecular Mechanisms and Microenvironmental Factors,” Frontiers in Cellular Neuroscience 12 (2018): 235.

[48]

C. Zhu, J. M. Kros, C. Cheng, and D. Mustafa, “The Contribution of Tumor-Associated Macrophages in Glioma Neo-Angiogenesis and Implications for Anti-Angiogenic Strategies,” Neuro-Oncology 19 (2017): 1435–1446.

[49]

L.-Q. Fu, W.-L. Du, M.-H. Cai, J.-Y. Yao, Y.-Y. Zhao, and X.-Z. Mou, “The Roles of Tumor-Associated Macrophages in Tumor Angiogenesis and Metastasis,” Cellular Immunology 353 (2020): 104119.

[50]

K. Wu, K. Lin, X. Li, et al., “Redefining Tumor-Associated Macrophage Subpopulations and Functions in the Tumor Microenvironment,” Frontiers in Immunology 11 (2020): 1731.

[51]

F. Khan, L. Pang, M. Dunterman, M. S. Lesniak, A. B. Heimberger, and P. Chen, “Macrophages and Microglia in Glioblastoma: Heterogeneity, Plasticity, and Therapy,” Journal of Clinical Investigation 133 (2023): e163446.

[52]

S. Batchu, K. A. Hanafy, N. Redjal, S. S. Godil, and A. J. Thomas, “Single-Cell Analysis Reveals Diversity of Tumor-Associated Macrophages and Their Interactions With T Lymphocytes in Glioblastoma,” Scientific Reports 13 (2023): 20874.

[53]

W. Wang, T. Li, Y. Cheng, et al., “Identification of Hypoxic Macrophages in Glioblastoma With Therapeutic Potential for Vasculature Normalization,” Cancer Cell 42 (2024): 815–832.e12.

[54]

Y. Yang, X. Jin, Y. Xie, et al., “The CEBPB + Glioblastoma Subcluster Specifically Drives the Formation of M2 Tumor-Associated Macrophages to Promote Malignancy Growth,” Theranostics 14 (2024): 4107–4126.

[55]

S. Agnihotri and G. Zadeh, “Metabolic Reprogramming in Glioblastoma: The Influence of Cancer Metabolism on Epigenetics and Unanswered Questions,” Neuro-Oncology 18 (2016): 160–172.

[56]

Y. Deng, Q. Chen, C. Wan, et al., “Microglia and Macrophage Metabolism: A Regulator of Cerebral Gliomas,” Cell & Bioscience 14 (2024): 49.

[57]

D. Wang, G. Li, T. Jiang, and W. Zhang, “Targeting the Lysine Lactylome for the Treatment of Glioma,” Cancer Biology & Medicine 21 (2024): 1095–1099.

[58]

A. J. Scott, A. Mittal, B. Meghdadi, et al., “Rewiring of Cortical Glucose Metabolism Fuels Human Brain Cancer Growth,” Nature 646 (2025): 413–422.

[59]

Y. Ma, Y. Huang, F. Hu, and K. Shu, “Lipid Metabolic Rewiring in Glioma‑Associated Microglia/Macrophages,” International Journal of Molecular Medicine 54 (2024): 102.

[60]

L. L. Lehrskov and R. H. Christensen, “The Role of Interleukin-6 in Glucose Homeostasis and Lipid Metabolism,” Seminars in Immunopathology 41 (2019): 491–499.

[61]

D. M. Rodrigues-Junior, C. Tsirigoti, K. Psatha, et al., “TGF-β Induces Cholesterol Accumulation to Regulate the Secretion of Tumor-Derived Extracellular Vesicles,” Journal of Experimental & Clinical Cancer Research 44 (2025): 42.

[62]

C. Corbet, E. Bastien, J. P. Santiago De Jesus, et al., “TGFβ2-Induced Formation of Lipid Droplets Supports Acidosis-Driven EMT and the Metastatic Spreading of Cancer Cells,” Nature Communications 11 (2020): 454.

[63]

N. Wang, Y. Yuan, T. Hu, H. Xu, and H. Piao, “Metabolism: An Important Player in Glioma Survival and Development,” Discover Oncology 15 (2024): 577.

[64]

D. Nan, W. Yao, L. Huang, et al., “Glutamine and Cancer: Metabolism, Immune Microenvironment, and Therapeutic Targets,” Cell Communication and Signaling 23 (2025): 45.

[65]

R. Jin, L. Neufeld, and T. L. McGaha, “Linking Macrophage Metabolism to Function in the Tumor Microenvironment,” Nature Cancer 6 (2025): 239–252.

[66]

X. Li, S. H. Møller, J. Park, et al., “Tumor-Instructed Glutamine Synthesis in Cancer-Associated Fibroblasts Promotes Pro-Tumor Macrophages,” Journal of Experimental Medicine 222 (2025): e20241426.

[67]

S. Liu, J. Yang, and Z. Wu, “The Regulatory Role of α -Ketoglutarate Metabolism in Macrophages,” Mediators of Inflammation 2021 (2021): 5577577.

[68]

K. Mehla and P. K. Singh, “Metabolic Regulation of Macrophage Polarization in Cancer,” Trends in Cancer 5 (2019): 822–834.

[69]

Y. Yang, B.-B. Cui, J. Li, et al., “Tricarboxylic Acid Cycle Metabolites: New Players in Macrophage,” Inflammation Research 73 (2024): 531–539.

[70]

M. Li, Q. Chen, M. Zhou, X. Li, Z. Wang, and J. Wang, “α-Ketoglutaric Acid Reprograms Macrophages by Altering Energy Metabolism to Promote the Regeneration of Small-Diameter Vascular Grafts,” ACS Biomaterials Science & Engineering 11 (2025): 518–530.

[71]

X. Zhao, T. Ren, S. Li, et al., “A New Perspective on the Therapeutic Potential of Tumor Metastasis: Targeting the Metabolic Interactions Between TAMs and Tumor Cells,” International Journal of Biological Sciences 20 (2024): 5109–5126.

[72]

H. Zhang, J. Liu, W. Yuan, et al., “Ammonia-Induced Lysosomal and Mitochondrial Damage Causes Cell Death of Effector CD8+ T Cells,” Nature Cell Biology 26 (2024): 1892–1902.

[73]

V. Y. Tu, A. Ayari, and R. S. O'Connor, “Beyond the Lactate Paradox: How Lactate and Acidity Impact T Cell Therapies Against Cancer,” Antibodies 10 (2021): 25.

[74]

R. Haas, J. Smith, V. Rocher-Ros, et al., “Lactate Regulates Metabolic and Pro-Inflammatory Circuits in Control of T Cell Migration and Effector Functions,” PLoS Biology 13 (2015): e1002202.

[75]

P. Apostolova and E. L. Pearce, “Lactic Acid and Lactate: Revisiting the Physiological Roles in the Tumor Microenvironment,” Trends in Immunology 43 (2022): 969–977.

[76]

X. Ma, Y. Gao, Y. Chen, et al., “M2-Type Macrophages Induce Tregs Generation by Activating the TGF-β/Smad Signalling Pathway to Promote Colorectal Cancer Development,” Oncotargets and Therapy 14 (2021): 5391–5402.

[77]

R. Noy and J. W. Pollard, “Tumor-Associated Macrophages: From Mechanisms to Therapy,” Immunity 41 (2014): 49–61.

[78]

N. Ochocka, P. Segit, K. A. Walentynowicz, et al., “Single-Cell RNA Sequencing Reveals Functional Heterogeneity of Glioma-Associated Brain Macrophages,” Nature Communications 12 (2021): 1151.

[79]

R. Du, K. V. Lu, C. Petritsch, et al., “HIF1α Induces the Recruitment of Bone Marrow-Derived Vascular Modulatory Cells to Regulate Tumor Angiogenesis and Invasion,” Cancer Cell 13 (2008): 206–220.

[80]

J. L. Ross, M. Puigdelloses-Vallcorba, G. Piñero, et al., “Microglia and Monocyte-Derived Macrophages Drive Progression of Pediatric High-Grade Gliomas and Are Transcriptionally Shaped by Histone Mutations,” Immunity 57 (2024): 2669–2687.e6.

[81]

A. V. Bonm, R. Ritterbusch, P. Throckmorton, and J. J. Graber, “Clinical Imaging for Diagnostic Challenges in the Management of Gliomas: A Review,” Journal of Neuroimaging 30 (2020): 139–145.

[82]

R. Guillevin, M. Naudin, P. Fayolle, et al., “Diagnostic and Therapeutic Issues in Glioma Using Imaging Data: The Challenge of Numerical Twinning,” Journal of Clinical Medicine 12 (2023): 7706.

[83]

A. Lerner, K. Palmer, T. Campion, et al., “Gliomas in Adults: Guidance on Investigations, Diagnosis, Treatment and Surveillance,” Clinical Medicine 24 (2024): 100240.

[84]

N. Lehman, W. Kowalska, M. Zarobkiewicz, et al., “Pro- vs. Anti-Inflammatory Features of Monocyte Subsets in Glioma Patients,” International Journal of Molecular Sciences 24 (2023): 1879.

[85]

F. Khan, L. Pang, M. Dunterman, M. S. Lesniak, A. B. Heimberger, and P. Chen, “Macrophages and Microglia in Glioblastoma: Heterogeneity, Plasticity, and Therapy,” Journal of Clinical Investigation 133 (2023): e163446.

[86]

M. van Eijk and J. Aerts, “The Unique Phenotype of Lipid-Laden Macrophages,” International Journal of Molecular Sciences 22 (2021): 4039.

[87]

D. J. Kloosterman, J. Erbani, M. Boon, et al., “Macrophage-Mediated Myelin Recycling Fuels Brain Cancer Malignancy,” Cell 187 (2024): 5336–5356.e30.

[88]

C. Giordano, L. Marrone, S. Romano, et al., “The FKBP51s Splice Isoform Predicts Unfavorable Prognosis in Patients With Glioblastoma,” Cancer Research Communications 4 (2024): 1296–1306.

[89]

Y. Wang, C. Xu, and Z. Zhang, “Prognostic Value of Pretreatment Lymphocyte-to-Monocyte Ratio in Patients With Glioma: A Meta-Analysis,” BMC Medicine 21 (2023): 486.

[90]

A. Hamm, H. Prenen, W. Van Delm, et al., “Tumour-Educated Circulating Monocytes Are Powerful Candidate Biomarkers for Diagnosis and Disease Follow-Up of Colorectal Cancer,” Gut 65 (2016): 990–1000.

[91]

V. Haage, M. Semtner, R. O. Vidal, et al., “Comprehensive Gene Expression Meta-Analysis Identifies Signature Genes That Distinguish Microglia From Peripheral Monocytes/Macrophages in Health and Glioma,” Acta Neuropathologica Communications 7 (2019): 20.

[92]

S. Müller, G. Kohanbash, S. J. Liu, et al., “Single-Cell Profiling of Human Gliomas Reveals Macrophage Ontogeny as a Basis for Regional Differences in Macrophage Activation in the Tumor Microenvironment,” Genome Biology 18 (2017): 234.

[93]

J. Zhou, N. Ji, G. Wang, et al., “Metabolic Detection of Malignant Brain Gliomas Through Plasma Lipidomic Analysis and Support Vector Machine-Based Machine Learning,” eBioMedicine 81 (2022): 104097.

[94]

W. Zhang, R. Dang, H. Liu, et al., “Machine Learning-Based Investigation of Regulated Cell Death for Predicting Prognosis and Immunotherapy Response in Glioma Patients,” Scientific Reports 14 (2024): 4173.

[95]

E. R. Abels, S. L. N. Maas, E. Tai, et al., “GlioM&M: Web-Based Tool for Studying Circulating and Infiltrating Monocytes and Macrophages in Glioma,” Scientific Reports 10 (2020): 9898.

[96]

L. Huang, J. Zhan, Y. Li, K. Huang, X. Zhu, and J. Li, “The Roles of Extracellular Vesicles in Gliomas: Challenge or Opportunity?,” Life Sciences 358 (2024): 123150.

[97]

S. Yang, Y. Sun, W. Liu, et al., “Exosomes in Glioma: Unraveling Their Roles in Progression, Diagnosis, and Therapy,” Cancers 16 (2024): 823.

[98]

V. Indira Chandran, S. Gopala, E. H. Venkat, M. Kjolby, and P. Nejsum, “Extracellular Vesicles in Glioblastoma: A Challenge and an Opportunity,” Npj Precision Oncology 8 (2024): 103.

[99]

G. Gutiérrez García, G. Galicia García, J. Zalapa Soto, et al., “Analysis of RNA Yield in Extracellular Vesicles Isolated by Membrane Affinity Column and Differential Ultracentrifugation,” PLoS ONE 15 (2020): e0238545.

[100]

L. M. Doyle and M. Z. Wang, “Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis,” Cells 8 (2019): 727.

[101]

S. Pandey and P. Yadav, “Liquid Biopsy in Cancer Management: Integrating Diagnostics and Clinical Applications,” Practical Laboratory Medicine 43 (2025): e00446.

[102]

E. B. Bell and J. Botham, “Antigen Transport. I. Demonstration and Characterization of Cells Laden With Antigen in Thoracic Duct Lymph and Blood,” Immunology 47 (1982): 477–487.

[103]

E. B. Bell, “The Migration of Antigen-Laden Cells,” Immunobiology 168 (1984): 325–337.

[104]

M. Liguori, E. Digifico, A. Vacchini, et al., “The Soluble Glycoprotein NMB (GPNMB) Produced by Macrophages Induces Cancer Stemness and Metastasis via CD44 and IL-33,” Cellular & Molecular Immunology 18 (2021): 711–722.

[105]

M. Biondini, A. Kiepas, L. El-Houjeiri, et al., “HSP90 inhibitors Induce GPNMB Cell-Surface Expression by Modulating Lysosomal Positioning and Sensitize Breast Cancer Cells to Glembatumumab vedotin,” Oncogene 41 (2022): 1701–1717.

[106]

J. V. Van Asperen, D. M. Fedorushkova, P. A. J. T. Robe, and E. M. Hol, “Investigation of Glial Fibrillary Acidic Protein (GFAP) in Body Fluids as a Potential Biomarker for Glioma: A Systematic Review and Meta-Analysis,” Biomarkers 27 (2022): 1–12.

[107]

J. P. Mcelroy, M.-A. Song, J. R. Barr, et al., “Lung Lipids Associated With Smoking and ECIG Use in a Cross-Sectional Study and Clinical Trial,” Respiratory Research 26 (2025): 193.

[108]

I. Florance and S. Ramasubbu, “Current Understanding on the Role of Lipids in Macrophages and Associated Diseases,” International Journal of Molecular Sciences 24 (2022): 589.

[109]

V. Di Nunno, L. Gatto, M. Aprile, S. Bartolini, A. Tosoni, and E. Franceschi, “Economic Income and Survival in Patients Affected by Glioblastoma: A Systematic Review and Meta-Analysis,” Neuro-Oncology Practice 11 (2024): 546–555.

[110]

V. Haage, M. Semtner, R. O. Vidal, et al., “Correction to: Comprehensive Gene Expression Meta-Analysis Identifies Signature Genes That Distinguish Microglia From Peripheral Monocytes/Macrophages in Health and Glioma,” Acta Neuropathologica Communications 8 (2020): 1.

[111]

Z. Huang, F. Yang, Y. Huang, X. Lin, W. Feng, and X. Tian, “Sorting and Identification of Circulating Tumor Cells of Gliomas With EGFR Antibody-Modified Immunomagnetic Microspheres,” AIP Advances 11 (2021): 025141.

[112]

N. Zhang, Z. Dai, W. Wu, et al., “The Predictive Value of Monocytes in Immune Microenvironment and Prognosis of Glioma Patients Based on Machine Learning,” Frontiers in Immunology 12 (2021): 656541.

[113]

Q. Zhou, Z. Zhou, Y. Guo, et al., “Machine Learning-Based Integration Develops a Hypoxia-Derived Signature for Improving Outcomes in Glioma,” Iscience 28 (2025): 112023.

[114]

Y. Zeng, J. Xie, N. Shangguan, et al., “CellFM: A Large-Scale Foundation Model Pre-Trained on Transcriptomics of 100 Million Human Cells,” Nature Communications 16 (2025): 4679.

[115]

V. O. Sviderskiy, V. Vasudevaraja, L. G. Dubois, et al., “Metabolic Profiling of Adult and Pediatric Gliomas Reveals Enriched Glucose Availability in Pediatric Gliomas and Increased Fatty Acid Oxidation in Adult Gliomas,” Acta Neuropathologica Communications 13 (2025): 61.

[116]

T. M. Malta, T. S. Sabedot, N. S. Morosini, et al., “The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen,” Cancer Research 84 (2024): 741–756.

[117]

C. Zhang, J. Deng, K. Li, et al., “Mononuclear Phagocyte System-Related Multi-Omics Features Yield Head and Neck Squamous Cell Carcinoma Subtypes With Distinct Overall Survival, Drug, and Immunotherapy Responses,” Journal of Cancer Research and Clinical Oncology 150 (2024): 37.

[118]

S. Zhao, B. Ye, H. Chi, C. Cheng, and J. Liu, “Identification of Peripheral Blood Immune Infiltration Signatures and Construction of Monocyte-Associated Signatures in Ovarian Cancer and Alzheimer's Disease Using Single-Cell Sequencing,” Heliyon 9 (2023): e17454.

[119]

P. K. Rahul, S. Krishnan, and S. Kummari, Signal Amplification Strategies for Biosensing of Clinically Important Analytes (Springer, 2024), p. 115–193.

[120]

T. D. Le, I. Suttikhana, and T. J. Ashaolu, “State of the Art on the Separation and Purification of Proteins by Magnetic Nanoparticles,” Journal of Nanobiotechnology 21 (2023): 363.

[121]

Y. Yu, Y. Mai, Y. Zheng, and L. Shi, “Assessing and Mitigating Batch Effects in Large-Scale Omics Studies,” Genome Biology 25 (2024): 254.

[122]

A. C. Dixson, T. R. Dawson, D. Di Vizio, and A. M. Weaver, “Context-Specific Regulation of Extracellular Vesicle Biogenesis and Cargo Selection,” Nature Reviews Molecular Cell Biology 24 (2023): 454–476.

[123]

R. D. C. Bravo-Miana, J. K. Arizaga-Echebarria, and D. Otaegui, “Central Nervous System-Derived Extracellular Vesicles: The next Generation of Neural Circulating Biomarkers?,” Translational Neurodegeneration 13 (2024): 32.

[124]

C.-H. Chen, S.-Y. Hsu, W.-J. Yu, C.-S. Chiang, and C.-F. Yu, “Distinct Roles of Small Extracellular Vesicles From Resident and Infiltrating Macrophages on Glioma Growth and Mobility,” Journal of Cancer 16 (2025): 969–981.

[125]

D. S. Lark, K. Stemmer, W. Ying, and C. Crewe, “A Brief Guide to Studying Extracellular Vesicle Function in the Context of Metabolism,” Nature Metabolism 6 (2024): 1839–1841.

[126]

G.-Y. Xie, Y.-H. Deng, C.-J. Liu, A.-Y. Guo, and Q. Lei, “Comprehensive Landscape of Small Non-Coding RNAs in Large and Small Extracellular Vesicles From Human Serum and Plasma,” Interdisciplinary Medicine 3 (2025): e20240073.

[127]

P. Gangadaran, A. Onkar, R. L. Rajendran, et al., “Noninvasive in Vivo Imaging of Macrophages: Understanding Tumor Microenvironments and Delivery of Therapeutics,” Biomarker Research 13 (2025): 20.

[128]

Z. Guo and Z. Cui, “Fluorescent Nanotechnology for in Vivo Imaging,” WIREs Nanomedicine and Nanobiotechnology 13 (2021): e1705.

[129]

H. Deng, L. Xu, J. Ju, X. Mo, G. Ge, and X. Zhu, “Multifunctional Nanoprobes for Macrophage Imaging,” Biomaterials 290 (2022): 121824.

[130]

E. J. Park, J. W. Song, H. J. Kim, et al., “In Vivo Imaging of Reactive Oxygen Species (ROS)-Producing Pro-Inflammatory Macrophages in Murine Carotid Atheromas Using a CD44-Targetable and ROS-Responsive Nanosensor,” Journal of Industrial and Engineering Chemistry 92 (2020): 158–166.

[131]

C. Cao, H. Yin, B. Yang, et al., “Intra-Operative Definition of Glioma Infiltrative Margins by Visualizing Immunosuppressive Tumor-Associated Macrophages,” Advanced Science 10 (2023): e2304020.

[132]

Z. Hu, C. Fang, B. Li, et al., “First-in-Human Liver-Tumour Surgery Guided by Multispectral Fluorescence Imaging in the Visible and Near-Infrared-I/II Windows,” Nature Biomedical Engineering 4 (2020): 259–271.

[133]

J. Liu, J. Peng, J. Jiang, and Y. Liu, “Clinical Immunotherapy in Glioma: Current Concepts, Challenges, and Future Perspectives,” Frontiers in Immunology 15 (2024): 1476436.

[134]

F. Tang, Y. Wang, Y. Zeng, A. Xiao, A. Tong, and J. Xu, “Tumor-Associated Macrophage-Related Strategies for Glioma Immunotherapy,” Npj Precision Oncology 7 (2023): 78.

[135]

Z. Song, Z. Zhao, X. Liu, et al., “Sphingosine Kinase 1 Promotes M2 Macrophage Infiltration and Enhances Glioma Cell Migration via the JAK2/STAT3 Pathway,” Scientific Reports 15 (2025): 4152.

[136]

X. Zhu, Y. Fang, Y. Chen, et al., “Interaction of Tumor-Associated Microglia/Macrophages and Cancer Stem Cells in Glioma,” Life Sciences 320 (2023): 121558.

[137]

D. Jiacheng, C. Jiayue, G. Ying, W. Shaohua, L. Wenhui, and H. Xinyu, “Research Progress and Challenges of the PD-1/PD-L1 Axis in Gliomas,” Cell & Bioscience 14 (2024): 123.

[138]

A. Baskaran, O. Kozel, O. Venkatesh, et al., “Immune Checkpoint Inhibitors in Glioblastoma IDHwt Treatment: A Systematic Review,” Cancers 16 (2024): 4148.

[139]

S. P. C. Hsu, Y.-C. Chen, H.-C. Chiang, et al., “Rapamycin and Hydroxychloroquine Combination Alters Macrophage Polarization and Sensitizes Glioblastoma to Immune Checkpoint Inhibitors,” Journal of Neuro-Oncology 146 (2020): 417–426.

[140]

X. Liu, X. Liu, X. Luo, et al., “Synergistic Strategies for Glioblastoma Treatment: CRISPR-Based Multigene Editing Combined With Immune Checkpoint Blockade,” Journal of Nanobiotechnology 23 (2025): 94.

[141]

M. Lin, Z. Yang, Y. Yang, et al., “CRISPR-Based in Situ Engineering Tumor Cells to Reprogram Macrophages for Effective Cancer Immunotherapy,” Nano Today 42 (2022): 101359.

[142]

Y. Chen, X. Chen, Y. Zhang, et al., “Macrophage-Specific in Vivo RNA Editing Promotes Phagocytosis and Antitumor Immunity in Mice,” Science Translational Medicine 17 (2025): eadl5800.

[143]

H. E. Marei, “Multimodal Targeting of Glioma With Functionalized Nanoparticles,” Cancer Cell International 22 (2022): 265.

[144]

H. R. Mendez-Gomez, A. Devries, P. Castillo, et al., “RNA Aggregates Harness the Danger Response for Potent Cancer Immunotherapy,” Cell 187 (2024): 2521–2535.e21.

[145]

X. Wang, H. Ding, Z. Li, et al., “Exploration and Functionalization of M1-Macrophage Extracellular Vesicles for Effective Accumulation in Glioblastoma and Strong Synergistic Therapeutic Effects,” Signal Transduction and Targeted Therapy 7 (2022): 74.

[146]

J. Lin, Z. Lin, L. Liu, W. Lin, X. Xie, and X. Zhang, “Enhancing Glioma-Specific Drug Delivery Through Self-Assembly of Macrophage Membrane and Targeted Polymer Assisted by Low-Frequency Ultrasound Irradiation,” Materials Today Bio 26 (2024): 101067.

[147]

Q. Guo and Z. M. Qian, “Macrophage Based Drug Delivery: Key Challenges and Strategies,” Bioactive Materials 38 (2024): 55–72.

[148]

Y. Pan, Y. Yu, X. Wang, and T. Zhang, “Tumor-Associated Macrophages in Tumor Immunity,” Frontiers in Immunology 11 (2020): 583084.

[149]

P. Zheng, J. He, Y. Fu, et al., “Engineered Bacterial Biomimetic Vesicles Reprogram Tumor-Associated Macrophages and Remodel Tumor Microenvironment to Promote Innate and Adaptive Antitumor Immune Responses,” ACS Nano 18 (2024): 6863–6886.

[150]

Z. Tian, X. Wang, S. Chen, Z. Guo, J. Di, and C. Xiang, “Mitochondria-Targeted Biomaterials-Regulating Macrophage Polarization Opens New Perspectives for Disease Treatment,” International Journal of Nanomedicine 20 (2025): 1509–1528.

[151]

A. Pant, B. Hwa-Lin Bergsneider, S. Srivastava, et al., “CCR2 and CCR5 Co-Inhibition Modulates Immunosuppressive Myeloid Milieu in Glioma and Synergizes With anti-PD-1 Therapy,” Oncoimmunology 13 (2024): 2338965.

[152]

V. C. Brom, C. Burger, D. C. Wirtz, and F. A. Schildberg, “The Role of Immune Checkpoint Molecules on Macrophages in Cancer, Infection, and Autoimmune Pathologies,” Frontiers in Immunology 13 (2022): 837645.

[153]

F. Yang, M. N. Akhtar, D. Zhang, et al., “An Immunosuppressive Vascular Niche Drives Macrophage Polarization and Immunotherapy Resistance in Glioblastoma,” Science Advances 10 (2024): eadj4678.

[154]

W. Zhang, M. Wang, W. Tang, et al., “Nanoparticle-Laden Macrophages for Tumor-Tropic Drug Delivery,” Advanced Materials 34 (2022): e2109925.

[155]

B. G. Carvalho, A. Nakayama, H. Miwa, et al., “Gelatin Methacryloyl Granular Scaffolds for Localized mRNA Delivery,” Aggregate 5 (2024): e464.

[156]

S. Cai, M. Li, J. Ye, et al., “Multifunctional Biomimetic Nanotherapeutics for Anti-Oxidative and Anti-Inflammatory Synergistic Therapy of Corneal Neovascularization,” Aggregate 6 (2025): e70034.

[157]

P. Zhao, Y. Wang, X. Kang, et al., “Dual-Targeting Biomimetic Delivery for Anti-Glioma Activity via Remodeling the Tumor Microenvironment and Directing Macrophage-Mediated Immunotherapy,” Chemical Science 9 (2018): 2674–2689.

[158]

Y. Guo, L. Jin, Z. Shen, et al., “Biomimetic Membrane Vesicles Reprogram Microglia Polarization and Remodel the Immunosuppressive Microenvironment of Glioblastoma via PERK/HIF-1α/Glycolysis Pathway,” Advanced Healthcare Materials 14 (2025): e2404782.

[159]

J. Kuang, Z. Rao, D. Zheng, et al., “Nanoparticles Hitchhike on Monocytes for Glioblastoma Treatment after Low-Dose Radiotherapy,” ACS Nano 17 (2023): 13333–13347.

[160]

Y. Wang, J. Zhan, J. Huang, et al., “Dynamic Responsiveness of Self-Assembling Peptide-Based Nano-Drug Systems,” Interdisciplinary Medicine 1 (2023): e20220005.

[161]

M. R. Jenkins and K. J. Drummond, “CAR T-Cell Therapy for Glioblastoma,” New England Journal of Medicine 390 (2024): 1329–1332.

[162]

Z. Wei, X. Zhang, T. Yong, et al., “Boosting Anti-PD-1 Therapy With Metformin-Loaded Macrophage-Derived Microparticles,” Nature Communications 12 (2021): 440.

[163]

V. Governa, K. G. De Oliveira, A. Bång-Rudenstam, et al., “Protumoral Lipid Droplet–Loaded Macrophages Are Enriched in Human Glioblastoma and Can be Therapeutically Targeted,” Science Translational Medicine 16 (2024): eadk1168.

[164]

Y. Han, H. Lu, Z. Gu, P. Guan, and Z. Liu, “In Situ Reprogramming of Tumor-Associated Macrophages Enhances Cancer Immunotherapy,” Nano Today 58 (2024): 102420.

[165]

A. Lin, C. J. Giuliano, A. Palladino, et al., “Off-Target Toxicity Is a Common Mechanism of Action of Cancer Drugs Undergoing Clinical Trials,” Science Translational Medicine 11 (2019): eaaw8412.

[166]

H. M. Nguyen, K. Huang, Y. Cui, H. Shim, and H. Wulff, “BPS2025 - Off-Target Effects of Piezo1 Agonistfs on Macrophages,” Biophysical Journal 124 (2025): 603a–604a.

[167]

F. Afrashteh, S. Seyedpour, and N. Rezaei, “The Therapeutic Effect of mRNA Vaccines in Glioma: A Comprehensive Review,” Expert Review of Clinical Immunology 21 (2025): 603–615.

[168]

M. Vara-Pérez and K. Movahedi, “Border-Associated Macrophages as Gatekeepers of Brain Homeostasis and Immunity,” Immunity 58 (2025): 1085–1100.

[169]

I. Noorani and J. de la Rosa, “Breaking Barriers for Glioblastoma With a Path to Enhanced Drug Delivery,” Nature Communications 14 (2023): 5909.

[170]

L. Pang, J. Qin, L. Han, et al., “Exploiting Macrophages as Targeted Carrier to Guide Nanoparticles Into Glioma,” Oncotarget 7 (2016): 37081–37091.

[171]

D. Zhu, W. J. Kim, H. Lee, X. Bao, and P. Kim, “Engineering CAR-T Therapeutics for Enhanced Solid Tumor Targeting,” Advanced Materials 37 (2025): 2414882.

[172]

N. Li, S. Geng, Z.-Z. Dong, et al., “A New Era of Cancer Immunotherapy: Combining Revolutionary Technologies for Enhanced CAR-M Therapy,” Molecular Cancer 23 (2024): 117.

[173]

M. B. Zewail, G. Yang, Y. Fan, Y. Hui, C.-X. Zhao, and Y. Liu, “Cell Membrane-Coated Lipid Nanoparticles for Drug Delivery,” Aggregate 6 (2025): e70054.

[174]

S. Rayamajhi, T. D. T. Nguyen, R. Marasini, and S. Aryal, “Macrophage-Derived Exosome-Mimetic Hybrid Vesicles for Tumor Targeted Drug Delivery,” Acta Biomaterialia 94 (2019): 482–494.

[175]

J. Lai, G. Deng, Z. Sun, et al., “Scaffolds Biomimicking Macrophages for a Glioblastoma NIR-Ib Imaging Guided Photothermal Therapeutic Strategy by Crossing Blood-Brain Barrier,” Biomaterials 211 (2019): 48–56.

[176]

Z. A. I. Mazrad, A. Refaat, J. P. Morrow, et al., “Folic Acid-Conjugated Brush Polymers Show Enhanced Blood–Brain Barrier Crossing in Static and Dynamic in Vitro Models Toward Brain Cancer Targeting Therapy,” ACS Biomaterials Science & Engineering 10 (2024): 2894–2910.

[177]

D. Choi, G. Go, D.-K. Kim, et al., “Quantitative Proteomic Analysis of Trypsin-Treated Extracellular Vesicles to Identify the Real-Vesicular Proteins,” Journal of Extracellular Vesicles 9 (2020): 1757209.

[178]

Y. Yu, Y. Peng, W.-T. Shen, et al., “Hybrid Cell Membrane-Coated Nanoparticles for Biomedical Applications,” Small Structures 5 (2024): 2300473.

[179]

O. Eladarousy, Z. Zibara, K. Hussari, N. Al Helou, and R. Nicolas, “Optimizing Plasmonic Photothermal Therapy a Numerical Study on Tissue Specific Thermal and Optical Properties for Cancer Treatment,” Scientific Reports 15 (2025): 17897.

[180]

Y. Wang, M. Zhao, S. Liu, et al., “Macrophage-Derived Extracellular Vesicles: Diverse Mediators of Pathology and Therapeutics in Multiple Diseases,” Cell Death & Disease 11 (2020): 924.

[181]

T. Liang, R. Zhang, X. Liu, et al., “Recent Advances in Macrophage-Mediated Drug Delivery Systems,” International Journal of Nanomedicine 16 (2021): 2703–2714.

[182]

W. Wang, K. Hu, J. Xue, et al., “In Vivo FAP-CAR Macrophages Enhance Chemotherapy and Immunotherapy Against Pancreatic Cancer by Removing the Fibrosis Barrier,” Journal of Controlled Release 384 (2025): 113888.

[183]

M. Xu, L. Bai, M. Sun, et al., “ROS-Responsive Biomimetic Nanocomplexes of Liposomes and Macrophage-Derived Exosomes for Combination Breast Cancer Therapy,” International Journal of Nanomedicine 20 (2025): 5161–5180.

[184]

S. Estes, K. Konstantinov, and J. D. Young, “Manufactured Extracellular Vesicles as Human Therapeutics: Challenges, Advances, and Opportunities,” Current Opinion in Biotechnology 77 (2022): 102776.

[185]

C. Guo, X. Ma, F. Gao, and Y. Guo, “Off-Target Effects in CRISPR/Cas9 Gene Editing,” Frontiers in Bioengineering and Biotechnology 11 (2023): 1143157.

[186]

N. Ochocka, P. Segit, K. A. Walentynowicz, et al., “Single-Cell RNA Sequencing Reveals Functional Heterogeneity of Glioma-Associated Brain Macrophages,” Nature Communications 12 (2021): 1151.

[187]

S. M. A. Elazim, M. H. Elkholy, A. Elgarhy, et al., “Enhancing Stability and Power Quality in Electric Vehicle Charging Stations Powered by Hybrid Energy Sources Through Harmonic Mitigation and Load Management,” Scientific Reports 15 (2025): 28077.

[188]

R. Crescitelli, J. Falcon-Perez, A. Hendrix, et al., “Reproducibility of Extracellular Vesicle Research,” Journal of Extracellular Vesicles 14 (2025): e70036.

[189]

Y. Huang, T. Arab, A. E. Russell, et al., “Toward a Human Brain Extracellular Vesicle Atlas: Characteristics of Extracellular Vesicles From Different Brain Regions, Including Small RNA and Protein Profiles,” Interdisciplinary Medicine 1 (2023): e20230016.

[190]

X. Liu, M. Wang, Y. Jiang, et al., “Magnetic Resonance Imaging Nanoprobe Quantifies Nitric Oxide for Evaluating M1/M2 Macrophage Polarization and Prognosis of Cancer Treatments,” ACS Nano 17 (2023): 24854–24866.

[191]

E. Liljedahl, E. Konradsson, E. Gustafsson, et al., “Long-Term Anti-Tumor Effects Following both Conventional Radiotherapy and FLASH in Fully Immunocompetent Animals With Glioblastoma,” Scientific Reports 12 (2022): 12285.

[192]

B. J. Schneider, J. Naidoo, B. D. Santomasso, et al., “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update,” Journal of Clinical Oncology 39 (2021): 4073–4126.

[193]

M. Sun, M. Bialasek, M. Mayoux, et al., “Adoptive Cell Therapy With Macrophage-Drug Conjugates Facilitates Cytotoxic Drug Transfer and Immune Activation in Glioblastoma Models,” Science Translational Medicine 17 (2025): eadr4058.

[194]

H. Zhang, W. Zhu, W. Pan, X. Wan, N. Li, and B. Tang, “Surface-Engineered Nanoshuttles Hijack Macrophages in Vivo to Boost Blood–Brain Barrier Penetration and Immunomodulation for Targeted Glioblastoma Therapy,” ACS Nano 19 (2025): 29737–29749.

RIGHTS & PERMISSIONS

2025 The Author(s). Aggregate published by SCUT, AIEI, and John Wiley & Sons Australia, Ltd.

PDF

3

Accesses

0

Citation

Detail

Sections
Recommended

/