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Cancers
Special Issues
Immune Microenvironment and Immunotherapy in Malignant Brain Tumors
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Immune Microenvironment and Immunotherapy in Malignant Brain Tumors

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: 30 April 2026 | Viewed by 3389

Special Issue Editors

Dr. Masaki Terabe

E-Mail Website
Guest Editor
National Cancer Institute (NCI), Bethesda, MD, USA
Interests: cancer immunology; immunotherapy brain; spine cancer tumor immunology glioblastoma natural killer T-cells (NKTs)
Prof. Dr. Mark R. Gilbert

E-Mail Website
Co-Guest Editor
National Cancer Institute (NCI), Bethesda, MD, USA
Interests: rare tumors cancer immunology; immunotherapy brain; spine cancer combination immunotherapy ependymoma cancer patient out-comes

Special Issue Information

Dear Colleagues,

Immunotherapy has revolutionized cancer treatment in the last decade by demonstrating the power of the immune system to fight against cancer. Although immunotherapy has brought benefits to patients with many cancer types, patients with brain cancer have not yet experienced these benefits. The brain has a unique tissue immune microenvironment, including the blood–brain barrier, unique resident myeloid cells called microglia and neurons. To improve the efficacy of immunotherapy against brain cancer, we need to better understand the immunobiology of these cancers. Emerging data suggest that the interaction of immune cells not only with other immune cells or cancer cells but also with other cell types, such as neurons and blood vessel cells, significantly impacts brain tumor immunity. There are other factors, such as sex and age, that also could have a significant impact on brain tumor immunity. This Special Issue aims to provide comprehensive information on the current understanding of the immune microenvironment of brain cancer, both primary and metastatic, and potential immunotherapeutic approaches.

Dr. Masaki Terabe
Prof. Dr. Mark R. Gilbert
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • glioma
  • brain metastasis
  • primary brain cancer
  • tumor immunity
  • neuroimmunology
  • immune microenvi-ronment
  • T cells
  • myeloid cells
  • cancer neuroscience

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Published Papers (3 papers)

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Research

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12 pages, 2193 KiB  
Article
Ultrasonic Aspiration-Acquired Glioblastoma Tissue Preserves Lymphocyte Phenotype and Viability, Supporting Its Use for Immunological Studies
by Eftychia Stavrakaki, Zineb Belcaid, Rutger K. Balvers, Lisette B. Vogelezang, Wouter B. L. van den Bossche, Demi Alderliesten, Karishma Lila, Thierry P. P. van den Bosch, Jacques J. M. van Dongen, Reno Debets, Cristina Teodosio, Clemens M. F. Dirven and Martine L. M. Lamfers
Cancers 2025, 17(4), 603; https://doi.org/10.3390/cancers17040603 - 11 Feb 2025
Viewed by 1008
Abstract
Background and Objective: Access to high-quality patient-derived brain tumor tissues is instrumental for translational neuro-oncology research. Glioblastoma tumor material resected by ultrasonic aspiration (UA) during surgery offers an abundant source of material; however, it is generally not used for research experiments. We [...] Read more.
Background and Objective: Access to high-quality patient-derived brain tumor tissues is instrumental for translational neuro-oncology research. Glioblastoma tumor material resected by ultrasonic aspiration (UA) during surgery offers an abundant source of material; however, it is generally not used for research experiments. We hypothesize that UA-derived tumor tissue represents a source of tissue that accurately reflects the immune infiltrates of glioblastomas. Methods: In this study, we have utilized UA-derived tissue and performed a head-to-head comparison with paired resection tissue from the vital tumor core of the same patient. A combination of 16 fluorochrome-conjugated antibodies was designed to identify tumor-infiltrating T, B, and NK lymphocytes and characterize the TILs by spectral flow cytometry. Furthermore, a 5-plex panel was designed to spatially characterize the T cells, macrophages, and tumor cells on the paired UA and resection tissues. Results: UA-obtained cells exhibited a comparable yield and viability, as well as an abundance of tumor-infiltrating T, B, and NK lymphocytes compared to resection sample-derived cells. Importantly, we observed that there is a high concordance with respect to expression intensities of immune checkpoints by T cells in both types of tissue samples. Conclusions: These findings underscore the feasibility and reliability of utilizing the immune infiltrates from ultrasonic aspiration-acquired glioblastoma tissue. Full article
(This article belongs to the Special Issue Immune Microenvironment and Immunotherapy in Malignant Brain Tumors)
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Review

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20 pages, 1962 KiB  
Review
The Basis for Targeting the Tumor Macrophage Compartment in Glioblastoma Immunotherapy
by Thomas Eckert, Chase Walton, Marcus Bell, Coulter Small, Nathan C. Rowland, Charlotte Rivers, Alicia Zukas, Scott Lindhorst, Peter Fecci and Ben A. Strickland
Cancers 2025, 17(10), 1631; https://doi.org/10.3390/cancers17101631 - 12 May 2025
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Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Immune Microenvironment and Immunotherapy in Malignant Brain Tumors)
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18 pages, 978 KiB  
Review
Immune Resistance in Glioblastoma: Understanding the Barriers to ICI and CAR-T Cell Therapy
by Thomas Eckert, M. S. Zobaer, Jessie Boulos, Angela Alexander-Bryant, Tiffany G. Baker, Charlotte Rivers, Arabinda Das, William A. Vandergrift, Jaime Martinez, Alicia Zukas, Scott M. Lindhorst, Sunil Patel, Ben Strickland and Nathan C. Rowland
Cancers 2025, 17(3), 462; https://doi.org/10.3390/cancers17030462 - 29 Jan 2025
Viewed by 1617
Abstract
Background: Glioblastoma (GBM) is the most common primary malignant brain tumor, with fewer than 5% of patients surviving five years after diagnosis. The introduction of immune checkpoint inhibitors (ICIs), followed by chimeric antigen receptor (CAR) T-cell therapy, marked major advancements in oncology. Despite [...] Read more.
Background: Glioblastoma (GBM) is the most common primary malignant brain tumor, with fewer than 5% of patients surviving five years after diagnosis. The introduction of immune checkpoint inhibitors (ICIs), followed by chimeric antigen receptor (CAR) T-cell therapy, marked major advancements in oncology. Despite demonstrating efficacy in other blood and solid cancers, these therapies have yielded limited success in clinical trials for both newly diagnosed and recurrent GBM. A deeper understanding of GBM’s resistance to immunotherapy is essential for enhancing treatment responses and translating results seen in other cancer models. Objectives: In this review, we examine clinical trial outcomes involving ICIs and CAR-T for GBM patients and explore the evasive mechanisms of GBM and the tumor microenvironment. Findings and Discussion: Multiple clinical trials investigating ICIs in GBM have shown poor outcomes, with no significant improvement in progression-free survival (PFS) or overall survival (OS). Results from smaller case studies with CAR-T therapy have warranted further investigation. However, no large-scale trials or robust studies have yet established these immunotherapeutic approaches as definitive treatment strategies. Future research should shift focus from addressing the scarcity of functional T cells to exploiting the abundant myeloid-derived cells within the tumor microenvironment. Conclusions: Translating these therapies into effective treatments for glioblastoma in humans remains a significant challenge. The highly immunosuppressive nature of GBM and its tumor microenvironment continue to hinder the success of these innovative immunotherapeutic approaches. Targeting the myeloid-derived compartment may lead to more robust and sustained immune responses. Full article
(This article belongs to the Special Issue Immune Microenvironment and Immunotherapy in Malignant Brain Tumors)
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