bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2026–03–01
ten papers selected by
Oltea Sampetrean, Keio University
  1. Pharmacological induction of mitochondrial stress counteracts therapy resistance in glioblastoma stem-like cells.
  2. Mitochondria transfer in Glioblastoma.
  3. The dynamic myeloid-enriched microenvironment of glioblastoma: a major challenge to immunotherapy efficacy.
  4. In Vivo Selection of anti-glioblastoma DNA aptamer-drug conjugates in an orthotopic patient-derived xenograft model.
  5. Progenitor Types in the Human Cortex in Normal Development and Glioblastoma.
  6. Glioblastoma-secreted C1QL1 orchestrates tumor microtube expansion and neural synaptic pruning to drive malignant synapse formation and recurrence.
  7. Oncolytic Zika virus therapy leverages CCR2+ monocytes to boost anti-glioblastoma T cell responses.
  8. TIGIT expression dictates the immunosuppressive reprogramming of myeloid cells in glioblastoma.
  9. Ketogenic diet therapy for high-grade gliomas combined with standard treatment using an angiogenesis inhibitor: An exploratory pilot study on feasibility.
  10. From the gut to the brain: The involvement of the gut microbiota in the development and progression of glioblastoma.
  1. bioRxiv. 2026 Feb 09. pii: 2026.02.05.704021. [Epub ahead of print]
    Pharmacological induction of mitochondrial stress counteracts therapy resistance in glioblastoma stem-like cells.
    Kenji Miki, Maged T Ghoche, Fanen Yuan, Fengping Li, Namya Manoj, Skyler Oken, Koji Yoshimoto, Pascal O Zinn, Sameer Agnihotri, Samuel K McBrayer, Kalil G Abdullah.
      Glioblastoma (GBM) stem-like cells (GSCs) contribute to therapeutic resistance and recurrence. We sought to define cellular processes underlying GSC resilience. We discovered that GSCs, unlike differentiated GBM cells (DGCs) or non-malignant neural cells, depend on mitochondrial function for survival. To target this vulnerability, we exploited doxycycline (DOXY), an antibiotic used in humans, to interfere with mitochondrial protein translation. DOXY induced cell death and inhibited sphere formation in GSCs, but not in DGCs or non-malignant cells, indicating a differentiation state-selective effect. Mechanistically, DOXY induced mitochondrial dysfunction and activated a stress-responsive apoptotic program involving HRI-mediated signaling. DOXY displayed antitumor efficacy in patient-derived GBM organoid and orthotopic xenograft models. Our study reveals that DOXY can selectively target undifferentiated glioma cells, informing a drug repurposing-based strategy.
    DOI:  https://doi.org/10.64898/2026.02.05.704021
  2. Neuro Oncol. 2026 Feb 23. pii: noag038. [Epub ahead of print]
    Mitochondria transfer in Glioblastoma.
    Simon Storevik, Mina Thue Augustsson, Shannon Moreino, Hanjo Köppe, Dionysios C Watson, Defne Bayik, Carolina De La Pena Fernandez, Amanda M Serapiglia, Nikhil Panicker, Justin Lathia, Hrvoje Miletic.
      Glioblastoma (GBM) is a highly aggressive and metabolically adaptable brain tumor characterized by profound cellular heterogeneity and therapy resistance. Recent research has uncovered the phenomenon of horizontal mitochondrial transfer (HMT) between GBM cells and their microenvironment, particularly astrocytes, which contributes to tumor progression, metabolic reprogramming, and treatment resistance. This review summarises current knowledge on mitochondrial exchange in GBM via tunneling nanotubes (TNTs), tumor microtubes (TMs) and potentially via extracellular vesicles (EVs). It also explores the functional consequences of HMT, including enhanced oxidative phosphorylation (OXPHOS), increased tumorigenicity, and altered therapeutic responses. This review highlights the need for further investigation into the molecular drivers and context-specific outcomes of mitochondrial transfer in GBM, with implications for novel therapeutic strategies.
    Keywords:  Glioblastoma; OXPHOS; mitochondria transfer; tumor microtubes; tunneling nanotubes
    DOI:  https://doi.org/10.1093/neuonc/noag038
  3. Front Immunol. 2026 ;17 1755073
    The dynamic myeloid-enriched microenvironment of glioblastoma: a major challenge to immunotherapy efficacy.
    Cindy Lamorlette, Cédric Boura, Sophie Pinel, Danièle Bensoussan, Gianpietro Dotti, Cécile Alanio, Loïc Reppel.
      Glioblastoma (GBM) is the most common and aggressive brain tumor in adults, and current treatments remain poorly efficient. In this context, immunotherapies may represent promising strategies. However, their efficacy is often limited by a strong negative impact of the tumor microenvironment (TME) of glioblastoma. Several factors such as tumor cells mutational profile, previous lines of conventional treatments, or biological factors, have been shown as involved in TME modulation. In this review, our goal is to give an overview of the main modulating factors of the TME of glioblastoma tumors. We will also highlight the importance of developing complex and integrative models to study this microenvironment. At the end, by highlighting critical components of the glioblastoma microenvironment, this review aims to support the development of next-generation, more effective and personalized immunotherapeutic strategies.
    Keywords:  glioblastoma; immunotherapy; microenvironment; modulating factors; myeloid cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1755073
  4. bioRxiv. 2026 Feb 18. pii: 2026.02.16.706148. [Epub ahead of print]
    In Vivo Selection of anti-glioblastoma DNA aptamer-drug conjugates in an orthotopic patient-derived xenograft model.
    Caroline D Doherty, Sonia Jain, Lauren L Ott, Katie K Bakken, Brandon A Wilbanks, Danielle M Burgenske, Keenan S Pearson, Jessica I Griffith, Zichen Tian, Jeffrey A Meridew, Saigopalakrishna S Yerneni, William F Elmquist, Jann N Sarkaria, L James Maher.
      Glioblastoma (GBM) is an aggressive, high-grade glioma with a near-universally fatal prognosis. Therapeutic failure is often attributed to the highly selective blood brain barrier (BBB), the diffuse infiltrative nature of the tumor, and the marked intratumoral heterogeneity of GBM. Although antibody drug conjugates ADCs have shown promise for high grade gliomas such as GBM, efficacy is limited by ADC size. Aptamers-short, synthetic, single-stranded DNA or RNA molecules-can be ∼6-fold lower in molecular weight than IgG antibodies and have the potential to cross the intact BBB. Unlike other nucleic acid-based therapies, aptamer function arises from three-dimensional shape rather than genetic coding. Here we aim to replace the targeting component of the ADC paradigm with a DNA aptamer, thus creating an aptamer-drug conjugate (ApDC). We employed in vivo SELEX using an orthotopic patient-derived xenograft (PDX) GBM mouse model and a vast (∼100 trillion 80-mer sequences) ApDC library. We report the results from this first in vivo ApDC selection of its kind. We characterize target tissue binding ex vivo , cell association, biodistribution, and pharmacokinetics from this selection. This study exemplifies an unbiased approach to a problem that rational design has yet to overcome, offering a new direction for GBM therapeutic development.
    DOI:  https://doi.org/10.64898/2026.02.16.706148
  5. Annu Rev Neurosci. 2026 Feb 27.
    Progenitor Types in the Human Cortex in Normal Development and Glioblastoma.
    Antoni Martija, Aparna Bhaduri.
      Human cortical development is dependent upon the structured proliferation and differentiation of progenitors into differentiated cell types. This process is tightly regulated by intrinsic and extrinsic cues, which converge to drive human-specific features of the cortex, most notably its expanded size and complexity. On the other hand, glioblastoma (GBM), a highly aggressive primary brain tumor, consists of a heterogeneous mix of neurodevelopmental-like cells that lack control of their proliferation and differentiation. These tumor cells exhibit uncontrollable growth and extreme plasticity, driven by somatic mutations, epigenetic rewiring, microenvironmental interactions, and maladaptive responses to therapy. Recent lineage-tracing and fate-mapping experiments have uncovered unconventional lineage relationships in both normal development and GBM, revealing new cell types along with their origins and progeny. We anticipate that neurodevelopmental perspectives will continue to deepen our understanding of GBM heterogeneity and plasticity, which can then inform the development of cell state reprogramming approaches for therapy.
    DOI:  https://doi.org/10.1146/annurev-neuro-102124-032845
  6. Cancer Discov. 2026 Feb 27.
    Glioblastoma-secreted C1QL1 orchestrates tumor microtube expansion and neural synaptic pruning to drive malignant synapse formation and recurrence.
    Chaoqiong Ding, Jiayi Dong, Zhenzhong Pan, Shijie Liu, Qiuyue Song, Gaoxia Yang, Yuling Peng, Chuanxing Xie, Zongyao Huang, Wei Yao, Mengnan Wu, Yi Zhong, Wei Zhang, Yan Zhang, Songhua Wang, Weiwei Ma, Yuan Wang.
      Glioblastoma (GBM) cells form neuron-to-glioma malignant synapses on neurite-like tumor microtubes (TMs), driving infiltrative growth and recurrence. The mechanisms underlying coordinated crosstalk among GBM cells and with neurons to favor malignant over normal synapses remain largely unknown. Here, we demonstrate that glioma-secreted C1QL1 is a key messenger for glioma-neuron and glioma-glioma crosstalk to drive TM expansion and malignant synapse formation. C1QL1 binds to its receptor BAI3 on neighboring neurons and GBM cells, activating Rac1-mediated cytoskeleton rearrangement to prune normal synapses and outgrow TMs, promoting malignant synapse and glioma network formation. Targeted treatment with a non-GEF-targeting, first-in-class Rac1 inhibitor rescues C1QL1-mediated synaptic pruning, inhibiting TMs and malignant synapses to impede glioma recurrence. Our findings elucidate how crosstalk among GBM cells and neurons allows infiltrating GBM cells to sculpt and integrate into the existing neural network, highlighting a therapeutic strategy against GBM recurrence through simultaneous inhibition of TMs and glioma-induced synaptic pruning.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-1123
  7. Neuro Oncol. 2026 Feb 23. pii: noag037. [Epub ahead of print]
    Oncolytic Zika virus therapy leverages CCR2+ monocytes to boost anti-glioblastoma T cell responses.
    Kevin S Cashman, Akshitkumar M Mistry, Ashwani Kesarwani, Amanda De Andrade Costa, Jonah Daneshmand, Hammad Ur Rehman, Matthias Mack, Michael S Diamond, Milan G Chheda, Sharmila Nair.
       BACKGROUND: Glioblastoma (GBM) is a lethal brain tumor with limited treatment options, largely due to profound immune suppression within the tumor microenvironment (TME), the failure of current immunotherapies to restore CD8+ T cell function, and persistence of glioma stem cells (GSCs) after treatment. Oncolytic Zika virus (ZIKV) is a promising therapeutic that selectively targets GSCs and remodels the TME to enhance anti-tumor CD8+ T cell responses. In this study we investigated how ZIKV efficacy in GBM is driven through monocytes.
    METHODS: We performed single-cell RNA sequencing and T cell receptor (TCR) sequencing to evaluate CD8+ T cell responses following ZIKV treatment. We used CellChat to define signaling networks between ZIKV-activated CCR2+ monocytes and CD8+ T cells in the TME. We used syngeneic, immunocompetent murine GBM models to validate mechanisms in vivo, applying genetic and antibody-based approaches to impair CCR2+ monocyte trafficking and function.
    RESULTS: ZIKV induced clonal expansion of tumor-infiltrating CD8+ T cells enriched in granzyme B and perforin-1, with reduced expression of exhaustion markers. CCR2+ monocytes were essential for the recruitment, proliferation, and effector functions of anti-tumor CD8+ T cells in the TME. Disruption of monocyte trafficking or function impaired these responses, diminishing cytotoxic activity and T cell recruitment.
    CONCLUSIONS: ZIKV-driven activation and recruitment of CCR2+ monocytes supports robust anti-tumor CD8+ T cell responses by enhancing cytotoxicity and limiting exhaustion. These findings highlight the previously unappreciated therapeutic potential of modulating monocyte-T cell crosstalk to overcome immune suppression in GBM.
    Keywords:  CCR2+ monocytes; CD8+ T cells; Zika virus; glioblastoma; myeloid
    DOI:  https://doi.org/10.1093/neuonc/noag037
  8. Neuro Oncol. 2026 Feb 25. pii: noag044. [Epub ahead of print]
    TIGIT expression dictates the immunosuppressive reprogramming of myeloid cells in glioblastoma.
    Mohammad Asad, Julio Inocencio, Stefan Mitrasinovic, Minori Aoki, Carly E Baker, Adilia Hormigo, Celina Crisman, Patrick Lasala, Emad Eskandar, Chandan Guha, Xingxing Zang, Ian F Parney, Benjamin T Himes.
       BACKGROUND: Immunotherapy has yet to make significant gains in glioblastoma (GBM) treatment, due in part to GBM-mediated immune suppression. Increasing evidence points to critical roles for tumor-derived extracellular vesicles (EVs) and immunosuppressive myeloid cells as key factors in this process.
    METHODS: Immunophenotyping of the tumor-immune microenvironment was performed using ultrasonic aspirate collected during GBM resection by high-dimensional flow cytometry. EVs collected from patient-derived GBM cell lines were used to condition myeloid cells collected from healthy donors to generate immunosuppressive myeloid cells. siRNA was used to knockdown TIGIT and/or NLRP3 expression prior to EV conditioning. T cell co-culture studies were performed with donor-matched T cells.
    RESULTS: Immune phenotyping of the tumor microenvironment and EV-conditioned myeloid cells revealed similar immunomodulatory protein expression across myeloid cell populations, with particularly elevated TIGIT expression. Knockdown of TIGIT reduced the immunosuppressive polarization of myeloid cells, resulting in improved T cell function. This finding proceeded in an NLRP3-dependent manner, with substantial co-expression of TIGIT and NLRP3 expression prior to knockdown, and concomitant knockdown of NLRP3 abrogating the effect of TIGIT knockdown. TIGIT expression correlated with increased IL-13 expression, and IL-13 blockade unmasked a pro-inflammatory myeloid cell phenotype.
    CONCLUSION: TIGIT expression in myeloid cells in the GBM microenvironment is a functional marker of immunosuppressive activity, with TIGIT knockdown reducing IL-13 expression and unmasking the pro-inflammatory activity of NLRP3. This study bolsters our understanding of the immunosuppressive complexities of the GBM microenvironment, and supports attenuation of immunosuppressive myeloid cell activity as a strategy to restore immune function in GBM.
    Keywords:  TIGIT; extracellular vesicles; glioblastoma; immunotherapy; myeloid cells
    DOI:  https://doi.org/10.1093/neuonc/noag044
  9. Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdaf264
    Ketogenic diet therapy for high-grade gliomas combined with standard treatment using an angiogenesis inhibitor: An exploratory pilot study on feasibility.
    Takashi Sasayama, Kazuhiro Tanaka, Hiroaki Nagashima, Michiko Takahashi, Misa Yamanishi, Misaki Kuroda, Satoko Tabuchi, Keisuke Hagihara, Shunsuke Yamanishi, Yusuke Ikeuchi, Yuichi Fujita, Hirohumi Iwahashi, Sayaka Hotta, Michiko Matsunaga, Shoji Sanada, Yoshihiro Muragaki, Masamitsu Nishihara.
       Background: Altered tumor metabolism has renewed interest in ketogenic strategies, despite limited clinical evidence in glioma. Whereas the ketogenic diet (KD) alone elevates intratumoral amino acids, bevacizumab (BEV) co-administration suppresses these metabolites and curtails tumor growth, pointing to a synergistic therapeutic potential.
    Methods: We conducted a clinical pilot study to evaluate the combination of KD and standard therapy, combining BEV, in patients with malignant glioma. A standardized modified ketogenic diet (mKD) regimen was implemented: carbohydrate intake was restricted to 10 g/day in the first week, 20 g/day in the following 2 months, and ≤30 g/day thereafter. MCT oil was administered at ≥50 mL/day, and ketone formula supplements were provided as needed. The primary endpoint was to assess safety and feasibility.
    Results: 10 patients were enrolled. The duration of mKD ranged from 63 to 1,954 days, with a median of 185 days. All patients showed a rapid increase in serum ketone levels and achieved therapeutically adequate glucose-ketone index values. All participants met the predefined safety criteria, and no severe adverse events were reported. One patient discontinued the diet owing to moderate abdominal pain. The objective response rate was 50%, and notably, one patient remained on mKD for more than 5 years without tumor recurrence. The median progression-free survival from mKD initiation was 9.5 months, and the median overall survival was 31 months.
    Conclusions: The combination of mKD and standard therapy with BEV was safe and feasible in patients with malignant glioma. Larger clinical trials are needed to determine its anti-tumor efficacy and clinical benefit.
    Keywords:  angiogenesis inhibitor; feasibility; ketogenic diet; malignant glioma; safety
    DOI:  https://doi.org/10.1093/noajnl/vdaf264
  10. Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdaf267
    From the gut to the brain: The involvement of the gut microbiota in the development and progression of glioblastoma.
    Daniela Toumazi, Christiana Charalambous, Constantina Constantinou, Nicoletta Nicolaou.
      Glioblastoma (GB) is the most malignant tumor in the adult central nervous system (CNS), presenting substantial treatment challenges due to its infiltrative nature, heterogeneity and immunosuppressive environment it creates. Current therapeutic efforts are focused on enhancing our understanding of GB and developing effective therapies. An emerging area of interest is the bidirectional gut-brain axis, which mediates communication between gut microbiota and CNS. The gut-brain axis allows the microbiota to modulate the immune system and inflammatory pathways through microbial metabolites, such as short-chain fatty acids (SCFAs) and tryptophan derivatives, promoting or suppressing GB progression. Understanding these interactions can lead to microbiota-targeted therapies for GB patients. Novel therapies, such as fecal microbiota transplantation to enhance immunotherapy response and using bacterial toxins to cross the blood-brain barrier, show promise in improving treatment-resistant GB treatment. Additionally, the role of probiotics and antibiotics on GB prognosis is being investigated. While more research is needed to understand the gut microbiota's role in GB, recent findings suggest promising directions for future therapies. This review examines the interplay between key immune system components and the microbiota in GB development and explores how this understanding could facilitate the development of novel therapeutic interventions.
    Keywords:  antibiotics; glioblastoma; gut microbiota; gut-brain axis; probiotics
    DOI:  https://doi.org/10.1093/noajnl/vdaf267
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