bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2026–04–19
six papers selected by
Oltea Sampetrean, Keio University
  1. Co-delivering macrophage engager mRNA and PD-L1 antibody via tumor-responsive nanoparticles for glioblastoma immunotherapy.
  2. NG2-targeting macrophages inhibit 3D invasion of patient-derived glioblastoma spheroids.
  3. Two to tango: Microglia in glioblastoma invasion.
  4. On-demand GLUT3 expression augments CAR T cell metabolic fitness and antitumor efficacy in preclinical models of glioblastoma.
  5. IL-6 underlies microenvironment immunosuppression and resistance to therapy in glioblastoma.
  6. Natural Product 4-Acetylantroquinonol B Enhances NK Cell-Mediated Immunity Against Glioblastoma.
  1. Nat Commun. 2026 Apr 11.
    Co-delivering macrophage engager mRNA and PD-L1 antibody via tumor-responsive nanoparticles for glioblastoma immunotherapy.
    Haoge Zhang, Jia Miao, Lin Gao, Xuhong Yang, Zhengcheng Yun, Lei Dong, Wanqing Cheng, Yuqi Wang, Hui Yang, Ying Zhou, Yini Zhu, Jinbing Xie.
      Bispecific immune cell engagers, particularly bispecific T-cell engagers, show limited efficacy in solid tumors such as glioblastoma (GBM) due to systemic toxicities, poor T cell infiltration, and restricted drug penetration. We develop PL@mBiME, a multifunctional lipid nanoparticle (LNP) platform that enables brain tumor-targeted delivery and sustained in vivo expression of mRNA encoding a bispecific macrophage engager (BiME). The BiME simultaneously targets ErbB2 on glioma cells and CD206 on M2 macrophages, reprogramming macrophages toward pro-inflammatory M1 phenotype while promoting macrophage-tumor cell bridging, enhancing tumor cell phagocytosis and antigen presentation. PL@mBiME incorporates pH-responsive charge reversal to improve tumor accumulation and lysosomal escape as well as glutathione-triggered release of surface-conjugated PD-L1 antibody to amplify anti-tumor immunity. Across multiple GBM models, this coordinated activation of innate and adaptive immunity induces tumor regression, prolongs survival, and generates durable immune memory without significant toxicity.
    DOI:  https://doi.org/10.1038/s41467-026-71646-y
  2. bioRxiv. 2026 Apr 07. pii: 2026.04.03.715398. [Epub ahead of print]
    NG2-targeting macrophages inhibit 3D invasion of patient-derived glioblastoma spheroids.
    Elena Kurudza, Sophia R S Varady, Daniel Greiner, James E Marvin, Alyse Ptacek, Melanie Rodriguez, Abhinava K Mishra, Gongping He, Gianpietro Dotti, Howard Colman, Melissa Q Reeves, Denise J Montell, Samuel H Cheshier, Minna Roh-Johnson.
      Engineering macrophages with chimeric antigen receptors is emerging as a promising cancer therapeutic. Chimeric antigen receptor-expressing macrophages (CAR-Ms) engineered to recognize tumor-specific antigens have been shown to inhibit tumor growth and activate adaptive immune responses, leading to robust tumor control in animal studies. Based on this work, clinical trials have been initiated. While the trials have shown promise, challenges remain. The dynamic interactions between CAR-Ms and cancer cells and the exact mechanisms driving anti-tumor effects remain poorly defined. Defining the dynamic interactions between CAR-Ms and cancer cells will provide critical insights for optimizing future CAR-M design and improving therapeutic efficacy. We sought to directly visualize CAR-M interactions with glioblastoma cells at high-resolution and in real-time using CAR-Ms engineered to recognize Neural-Glial Antigen 2 (NG2), an antigen expressed on glioblastoma cells. Using patient-derived glioblastoma cells, we formed glioblastoma spheroids and embedded them in a 3D matrix together with CAR-Ms. Using time-lapse microscopy, as expected, we found that NG2-targeting CAR-Ms engulfed glioblastoma cells. However, excitingly, we found that NG2-targeting CAR-Ms blocked >85% of glioblastoma cell invasion in 3D. This inhibition of glioblastoma invasion was not due to a significant change in CAR-M polarization states. Together, these data suggest that NG2-targeting CAR-Ms both engulf glioblastoma cells and block glioblastoma invasive behavior.
    DOI:  https://doi.org/10.64898/2026.04.03.715398
  3. Immunity. 2026 Apr 14. pii: S1074-7613(26)00127-5. [Epub ahead of print]59(4): 937-939
    Two to tango: Microglia in glioblastoma invasion.
    Donn A Van Deren, Malay Haldar.
      A lethal feature of glioblastoma is its ability to spread within the brain. In this issue of Immunity, Nebeling et al. use longitudinal three-photon imaging in an immunocompetent glioblastoma model to show that microglial responses at the far infiltration zone are spatially restricted and biphasic, with CX3CR1 signaling modulating tumor invasion dynamics.
    DOI:  https://doi.org/10.1016/j.immuni.2026.03.016
  4. Sci Transl Med. 2026 Apr 15. 18(845): eadu3532
    On-demand GLUT3 expression augments CAR T cell metabolic fitness and antitumor efficacy in preclinical models of glioblastoma.
    Junya Yamaguchi, Keisuke Watanabe, Akihiro Nakamura, Nina Yi-Tzu Lin, Sachi Maeda, Daisuke Sugiyama, Shinichiro Kato, Akihito Nagata, Hitomi Nishinakamura, Kota Itahashi, Shohei Koyama, Hiroyuki Mizoguchi, Yukihiro Shiraki, Atsushi Enomoto, Fumiharu Ohka, Kazuya Motomura, Yuichiro Tsukada, Masaaki Ito, Yuka Maeda, Ryuzo Ueda, Atsushi Natsume, Ryuta Saito, Hiroyoshi Nishikawa.
      The clinical success of chimeric antigen receptor T cell (CAR T cell) therapy in hematologic malignancies has prompted its application for refractory solid tumors, including glioblastoma (GBM). However, CAR T cell trials against solid tumors have failed to show clinical efficacy thus far. Here, we show that the dysfunction of CAR T cells in GBM is attributed, at least, in part, to glucose deficiency in the tumor microenvironment (TME) driven by the substantial consumption of glucose by cancer cells. Engineering CAR T cells to continuously express glucose transporter 3 (GLUT3), a high-affinity glucose transporter, restored their cytokine production and killing activity. However, although CAR T cells with stable GLUT3 expression induced tumor reduction in a preclinical GBM model, their overactivation led to adverse events and mouse death. In contrast, on-demand GLUT3-expressing CAR T cells, in which GLUT3 transcription was driven by the nuclear translocation of nuclear factor of activated T cells (NFAT) as a consequence of target antigen stimulation, exhibited enhanced metabolic fitness and increased antitumor efficacy, leading to long-lasting tumor control in intracranial human GBM cell xenograft models while preventing adverse events. We propose that on-demand enhancement of metabolic fitness, such as at the time of exposure to tumor antigens, is a concept for boosting the antitumor efficacy of CAR T cells against solid tumors.
    DOI:  https://doi.org/10.1126/scitranslmed.adu3532
  5. Cancer Res. 2026 Apr 13.
    IL-6 underlies microenvironment immunosuppression and resistance to therapy in glioblastoma.
    Jacob S Young, Nam Woo Cho, Calixto-Hope G Lucas, Hinda Najem, Kanish Mirchia, William C Chen, Courtney Tamaki, Harrshavasan Congivaram, Kyounghee Seo, Naomi Zakimi, Vikas Daggubati, Tim Casey-Clyde, Minh P Nguyen, Zenhong Chen, Joanna J Phillips, Tomoko Ozawa, Manish K Aghi, Jennie W Taylor, Joseph L DeRisi, Aparna Bhaduri, Mitchel S Berger, Amy B Heimberger, Nicholas A Butowski, Matthew H Spitzer, David R Raleigh.
      The glioblastoma tumor immune microenvironment (TIME) is an immunosuppressive barrier to therapy that encumbers glioblastoma responses to immune checkpoint inhibition (ICI). Immunosuppressive cytokines, pro-tumor macrophages and myeloid cells, and exhausted T-cells are all hallmarks of the glioblastoma TIME. Here we integrate spatial and single-cell analyses of patient-matched human glioblastoma samples before and after ICI with genetic, immunologic, single-cell, and pharmacologic studies in preclinical models to show that interleukin-6 (IL-6) neutralization reprograms the glioblastoma TIME to sensitize mouse glioblastoma allografts to ICI and radiotherapy. We find rare human glioblastomas that achieve clinical responses to ICI have lower pre-treatment IL-6 levels compared to glioblastomas that do not respond to ICI. Our data show that diverse immunostimulatory gene therapies suppress local IL-6 levels in mouse glioblastoma allografts, and that IL-6 from glioblastoma cells and the tumor microenvironment is associated with reduced survival in preclinical models and in patients. We show that IL-6 blockade with a neutralizing antibody transiently sensitizes mouse glioblastoma allografts to ICI by decreasing immunosuppressive Tregs, and by increasing MHCII+ monocytes, CD103+ migratory dendritic cells (DCs), CD11b+ conventional DCs, and effector CD8+ T cells. To translate these findings to a combination treatment strategy that could be used for patients, we show that IL-6 blockade plus ICI more durably sensitizes mouse glioblastoma allografts to immunostimulatory ablative radiotherapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-2922
  6. Cancer Med. 2026 Apr;15(4): e71832
    Natural Product 4-Acetylantroquinonol B Enhances NK Cell-Mediated Immunity Against Glioblastoma.
    Yuan-Chieh Yeh, Chuan-Hsin Chang, Cheng-Chi Lee, Tzong-Huei Lee, Yin-Cheng Huang.
      Glioblastoma (GBM) recurs rapidly despite surgery and radiochemotherapy and is associated with profound natural killer (NK) cell dysfunction. Adoptive NK cell transfer has emerged as a plausible immunotherapy for GBM and is being tested clinically; however, its efficacy is limited by the suppressive tumor microenvironment, low NK infiltration, and metabolic exhaustion. 4-Acetylantroquinonol B (4-AAQB), a ubiquinone derivative purified from Antrodia cinnamomea, has demonstrated antitumor and anti-inflammatory properties. These properties suggest that 4-AAQB may rescue or enhance NK cell activity against GBM cells. Therefore, we evaluated the effects of 4-AAQB on the cytotoxicity of NK-92 cells against human GBM cells using NK cell cytotoxicity assays. Treatment with 4-AAQB significantly enhanced the cytotoxicity of NK-92 cells against GBM cells, without affecting normal MRC5 fibroblasts. Additionally, in a GBM xenograft mouse model, 4-AAQB and NK-92 cells individually suppressed tumor growth, whereas their combination produced a synergistic antitumor effect without inducing liver or kidney toxicity. Bulk RNA sequencing of excised tumors revealed distinct differentially expressed genes in the combination group that were not shared with either monotherapy. Notably, the combined therapy upregulated immune effector genes involved in apoptotic cell clearance and NK cell maturation, while simultaneously downregulating key survival and resistance pathways. Furthermore, pathway analysis revealed suppression of autophagy and mitophagy, suggesting that 4-AAQB sensitizes GBM cells to immune-mediated apoptosis by disrupting intrinsic survival circuits. These findings support 4-AAQB as an orally administered adjuvant that enhances NK cell immunotherapy for GBM and warrant further translational development.
    Keywords:   Antrodia cinnamomea ; 4‐acetylantroquinonol B; anticancer effect; glioblastoma; natural killer cell
    DOI:  https://doi.org/10.1002/cam4.71832
This page is being maintained by Thomas Krichel. It was last updated on 2026‒04‒19 at 0:14.