bims-malgli 2026-03-22 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2026–03–22
eight papers selected by
Oltea Sampetrean, Keio University

Mismatch repair deficiency reshapes glioblastoma through immune suppression rather than hypermutation.
DNA Methylation Profiling Reveals a Novel Subtype Harboring IDH Mutation in H3-altered Gliomas.
Symbiotic exclusivity between CLOCK and TFPI2 drives stemness and immunosuppression in glioblastoma models.
Microglial fructose metabolism is essential for glioblastoma growth.
Combined Patch-clamp Electrophysiology and Single-Cell Genomic Analysis Reveal Spiking Tumor Cells at the Neocortical Glioblastoma Interface in Humans.
A blueprint for local and distal invasion programs in glioblastoma.
Synthetic SIGLEC9-based chimeric switch receptor augments the efficacy of CAR macrophages against glioblastoma.
NANP targeting radiosensitizes glioblastoma through TNFR1 sialylation-driven mesenchymal shift.

J Clin Invest. 2026 Mar 16. pii: e203730. [Epub ahead of print]136(6):

Mismatch repair deficiency reshapes glioblastoma through immune suppression rather than hypermutation.

Andrew Li, Thomas K Sears, Craig M Horbinski.

Mismatch repair (MMR) deficiency is classically associated with microsatellite instability, a high tumor mutational burden (TMB), and sensitivity to immune checkpoint blockade in cancer. In this issue of the JCI, Puigdelloses Vallcorba et al. reported that this paradigm does not hold true in glioblastoma (GBM). Using genetically engineered mouse models, the authors demonstrated that loss of core MMR genes was insufficient to induce hypermutation or improve survival rates with PD-1 blockade. Instead, mouse models of germline MMR deficiency accelerated malignant progression by promoting the immune milieu toward a myeloid cell-dominant and T cell-suppressed tumor microenvironment. Importantly, the imidazotetrazine agent N3-(2-fluoroethyl) imidazotetrazine (KL-50) bypassed MMR dependence and overcame temozolomide resistance. These findings suggest MMR deficiency in GBM as a driver of immune suppression rather than tumor immunogenicity and carry important implications for therapy selection.

DOI: https://doi.org/10.1172/JCI203730
Neuro Oncol. 2026 Mar 14. pii: noag054. [Epub ahead of print]

DNA Methylation Profiling Reveals a Novel Subtype Harboring IDH Mutation in H3-altered Gliomas.

Minjie Fu, Yuan Feng, Pin Sun, Muyuan You, Licheng Zhang, Hui Yang, Yi Zhang, Dan Ye, Jiguang Wang, Yue Xiong, Roel Verhaak, Ying Mao, Wei Hua.

   BACKGROUND: H3-altered gliomas, now recognized by WHO CNS5 as grade 4 neoplasms driven by histone H3 mutations (notably H3K27M and H3G34R/V), exhibit marked molecular heterogeneity, dismal survival, and resistance to standard therapies. Despite their classification as WHO grade 4 neoplasms, current stratification fails to capture their clinical and epigenetic diversity.
METHODS: We performed genome-wide DNA methylation profiling on 49 representative cases from a clinical cohort of 375 H3-altered gliomas, and validated subtype classifications using TCGA data. Single-cell RNA sequencing, ChIP-seq, and spatial transcriptomic analyses were employed to elucidate tumor-intrinsic programs and microenvironmental niches across subtypes.
RESULTS: Unsupervised clustering identified four robust DNA methylation-defined subtypes: DMG_K27M, GBM_RTK, DHG_G34, and IDH/H3_comut, a novel subtype harboring co-occurring IDH and H3 mutations. The IDH/H3_comut subtype exhibited global DNA hypermethylation, enrichment in neurodevelopmental gene programs, and significantly improved survival. In contrast, GBM_RTK tumors showed hypomethylation of cell-cycle enhancers and aggressive phenotypes, while DHG_G34 and DMG_K27M displayed subtype-specific epigenetic features. Single-cell transcriptomics revealed distinct lineage compositions and microenvironments, with IDH/H3_comut tumors enriched in NPC-like cells, and GBM_RTK in astrocyte-like and vascular mimicry programs. Clonal and spatial analyses uncovered a compartmentalized coexistence of IDH- and H3-mutant cells, suggesting cooperative rather than exclusive evolution.
CONCLUSIONS: Our study redefines H3-altered gliomas through methylation-based taxonomy, identifies a novel IDH/H3_comut subtype with favorable prognosis, and reveals subtype-specific therapeutic vulnerabilities, including potential responsiveness to hypomethylating agents or CDK4/6 inhibitors.

Keywords:  H3 alteration; IDH mutation; glioma; methylation; subtype

DOI:  https://doi.org/10.1093/neuonc/noag054
J Clin Invest. 2026 Mar 17. pii: e199056. [Epub ahead of print]

Symbiotic exclusivity between CLOCK and TFPI2 drives stemness and immunosuppression in glioblastoma models.

Fei Zhou, Lizhi Pang, Yang Liu, Fatima Khan, Peiwen Chen.

  Glioblastoma (GBM) is a highly aggressive brain tumor characterized by extensive crosstalk between glioblastoma stem cells (GSCs) and immunosuppressive microglia, with our previous work identifying CLOCK and TFPI2 as key regulators of this interaction. Here, we uncover a 'symbiotic exclusivity' pattern between CLOCK and TFPI2, showing that despite mutually exclusive amplifications, they sustain symbiotic regulatory interactions in GBM. The CLOCK-BMAL1 complex transcriptionally upregulates TFPI2, while TFPI2-driven hypoxia inducible factor 1 alpha (HIF1a) signaling activates nuclear factor kappa B (NF-kB) P65 to upregulate the CLOCK-BMAL1 complex, creating a positive feedback loop to promote stemness, immunosuppression, and tumor progression. Disrupting the CLOCK-TFPI2 interplay through dual inhibition of their downstream effectors reduces GSC stemness and immunosuppressive microglia, activates antitumor immunity, and synergizes with anti-PD1 therapy to achieve complete tumor regression in 50-62.5% of tumor-bearing mice. This study uncovers a promising therapeutic strategy for a broader subset of GBM patients with high expression of either CLOCK or TFPI2, and provides a framework for identifying 'symbiotic exclusivity' genes in cancer.

Keywords:  Adult stem cells; Cancer; Immunology; Immunotherapy; Oncology

DOI:  https://doi.org/10.1172/JCI199056
Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2521256123

Microglial fructose metabolism is essential for glioblastoma growth.

Leah K Billingham, Susan L DeLay, Yasmina Eshac, Tzu-Yi Chia, Shashwat Tripathi, Ian E Olson, Kaylee Zilinger, Jay Subbiah, Zhaoquan Wang, Nishanth S Sadagopan, Hinda Najem, Guillaume Cognet, Joshua L Katz, Ruochen Du, Khizar R Nandoliya, Lauren K Boland, Gustavo Ignacio Vázquez-Cervantes, Si Wang, Hanxiao Wan, Allie B Lipshutz, Alina R Murphy, Joseph Duffy, Irina V Balyasnikova, Peng Zhang, Dieter Henrik Heiland, Atique U Ahmed, Catalina Lee-Chang, Amy B Heimberger, Justin S A Perry, Alexander Muir, Navdeep S Chandel, Jason Miska.

  Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors in adults. Its immune microenvironment is dominated by tumor-associated macrophages, including both infiltrating monocytes and brain-resident microglia. While metabolic rewiring of infiltrating myeloid cells has been shown to support tumor progression, the role of microglial metabolism in GBM remains incompletely understood. Here, we demonstrate that microglia uniquely express the fructose transporter GLUT5 and are the only immune cells in the GBM microenvironment capable of metabolizing fructose. Using murine orthotopic glioma and Replication-Competent Avian sarcoma leuko virus Splice acceptor (RCAS)-derived tumor models, we show that global deletion of GLUT5 confers profound resistance to tumor growth. This effect is driven by loss of fructose metabolism in microglia and occurs independently of contributions from peripheral immune compartments. In GLUT5-deficient mice, tumors exhibit increased infiltration and activation of both innate and adaptive immunity, including enhanced antigen presentation, clonal expansion of CD8+ T cells, and increased cytokine production. Depletion of B-cells or CD8+ T cells abrogated survival phenotypes in knockout mice, demonstrating that GLUT5 suppresses adaptive immunity. These findings identify microglial fructose metabolism as a critical regulator of immune suppression in GBM and suggest that targeting this pathway may improve immunotherapeutic responses.

Keywords:  fructose metabolism; glioblastoma; microglia; redox homeostasis

DOI:  https://doi.org/10.1073/pnas.2521256123
Neuro Oncol. 2026 Mar 19. pii: noag059. [Epub ahead of print]

Combined Patch-clamp Electrophysiology and Single-Cell Genomic Analysis Reveal Spiking Tumor Cells at the Neocortical Glioblastoma Interface in Humans.

Tong Tong, Josephine D Hendriksen, Kirstine J Elbæk, Kata Molnar, Freja V Christiansen, Attila Ozsvar, Jens T Eschen, Francisco G Rodríguez-González, Ilayda D Pusat, Emilie Littau Christensen, Mads Rahbæk, Kathrine Pii Frederiksen, Søren O S Cortnum, Ann K Sindby, Kaare Meier, Nikola Mikic, Jens C H Sørensen, Jonathan T Ting, Marco Capogna, Bjarne W Kristensen, Jens R Nyengaard, Joachim Weischenfeldt, Wen-Hsien Hou, Anders R Korshøj.

   BACKGROUND: Electrophysiological features of glioblastoma cells (GBCs) remain largely elusive, challenging our comprehension of glioblastoma pathophysiology. Spiking GABAergic-OPC tumor cells were recently described in IDH-mutant glioma, correlating with prolonged patient survival. Here, we characterize single-cell features at the neocortical leading edge (LE) of glioblastoma patients using combined electrophysiological, morphological, and transcriptomic profiling.
METHODS: We examined GBCs and non-tumor cells using acute and cultured organotypic slices of cancer-infiltrated neocortical tissues from glioblastoma patients. Electrophysiological properties of LE cells were investigated using whole-cell patch-clamp recording, with dye loading to characterize single-cell morphology. We used Patch-seq to determine the transcriptomic features of recorded LE cells and discriminate tumor and non-tumor cells, followed by gene set enrichment analysis (GSEA) and CellChat to identify differential gene expression and signaling.
RESULTS: Upon depolarization, more than half of LE cells show aberrant action potentials (aAPs), akin to neurodevelopmental cells. Reconstructed LE cells have abnormal somatodendritic morphology. Patch-seq revealed that GBCs and non-tumor cells share a similar electrophysiological phenotype, including aAP generation, depolarized membrane potential, and elevated input resistance. Transcriptomic analysis shows that the aAP phenotype occurs across diverse GBC states and correlates with lower enrichment of proliferation-related pathways at the single-cell level, but higher enrichment of inflammatory/immune, angiogenic, and mesenchymal transition pathways. Non-tumor cells exhibit hybrid transcriptomic signatures, with predominantly neuronal but minor enrichment of astrocytic features.
CONCLUSION: We find electrophysiological aAP behavior of GBCs in human glioblastoma, closely resembling that of hybrid cells in IDH-mutant glioma, supporting the hypothesis of neuronal mimicry across different glioma types.

Keywords:  Action potential; Cancer Neuroscience; Glioblastoma; Organotypic slice culture; Patch-seq

DOI:  https://doi.org/10.1093/neuonc/noag059
Nat Commun. 2026 Mar 17.

A blueprint for local and distal invasion programs in glioblastoma.

Rony Chanoch-Myers, Toshiro Hara, Alissa C Greenwald, Rouven Hoefflin, Lillian Bussema, Hannah R Weisman, Edwin Nieblas-Bedolla, Jahnavi Gurramkonda, Zhibek Bekezhankyzy, Alexander Jucht, Ester Calvo Fernández, Avishay Spitzer, Jeremy Man Hon Fung, Biella Chiara, Wajd N Al-Holou, Sandra Camelo-Piragua, Jinan Behnan, Rossella Galli, Hiroaki Wakimoto, Mario L Suvà, Itay Tirosh.

Glioblastoma invasion into brain parenchyma presents significant challenges for treatment but remains poorly understood. In this study, we combine single-cell RNA sequencing, spatial transcriptomics, and multiplexed imaging of orthotopic xenograft models to investigate glioblastoma invasion. We first screen 20 patient-derived gliomasphere models for their distal (i.e., extending to the contralateral hemisphere) and local invasive potential in mice. We show that models with distal invasion potential are enriched with oligodendrocyte progenitor-like cells, while models with only local invasion potential are enriched with mesenchymal-like cells. These patterns reflect predominantly peri-axonal vs peri-vascular invasion routes, respectively. Next, we analyze the transcriptomes of invading cells within models (compared to tumor core) and identify programs associated with distal and local invasion. Thus, we decouple transcriptional features associated with invasion potential from those associated with the process of invasion. We validate our findings by spatial transcriptomics and multiplexed imaging, further describing the spatial niche of invasive cells. Taken together, our results provide a blueprint for the invasive potential of glioblastoma cell states and of the programs associated with invasion across different scales.

DOI: https://doi.org/10.1038/s41467-026-70470-8
Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2519819123

Synthetic SIGLEC9-based chimeric switch receptor augments the efficacy of CAR macrophages against glioblastoma.

Zhipeng Fu, Xiaotian Zhao, Qikang Zhang, Maosen Han, Jing Zhang, Zhenmei Yang, Yan Wang, Zichao Yao, Ying Liu, Chunwei Tang, Kaiyan Xi, Zhanyan Liu, Yi Zhang, Kun Zhao, Na Li, Yulin Zhang, Yudong Song, Xinyi Jiang, Chen Chen.

  Chimeric antigen receptor macrophage (CAR-M) therapy represents a promising therapeutic approach for treating glioblastoma multiforme (GBM). However, durable antitumorigenic macrophage phenotype of CAR-Ms is limited by the highly immunosuppressive tumor microenvironment (TME), wherein Siglec-sialic acid signaling directly drives macrophage polarization toward a protumorigenic phenotype. We here report an in situ synthetic SIGLEC9-based chimeric switch receptor (CSR) for diverting the inhibitory signal into positive ones, augmenting the sustained proinflammatory phenotype and tumoricidal immunity of CAR-Ms in the GBM niche. Specifically, our results showed that macrophage-targeted ionizable lipid nanoparticles efficiently introduce dual circRNAs into macrophages to generate CSR functionalized CAR-Ms in vitro and in vivo. The modified macrophages maintained a proinflammatory state, exhibited superior phagocytic activity, resulting in rapid and efficient eradication of IL13Rα2-positive tumor cells. Moreover, an injectable nanoparticle-hydrogel system for reprogramming macrophages surrounding the glioma resection cavity initiated a locoregional antitumor immune response and elicited robust long-term immunological memory, inhibiting tumor relapse in the postoperative GBM model. In sum, our findings establish that the engineered SIGLEC9-based CSR significantly promotes the maintenance of an antitumoral phenotype of CAR-Ms in the hypersialylated acidic TME, contributing to the improvement of engineered macrophage-based immunotherapy against GBM.

Keywords:  SIGLEC9; chimeric antigen receptor macrophages; chimeric switch receptor; glioblastoma

DOI:  https://doi.org/10.1073/pnas.2519819123
Nat Commun. 2026 Mar 18.

NANP targeting radiosensitizes glioblastoma through TNFR1 sialylation-driven mesenchymal shift.

Yingwen Ding, Ze-Yan Zhang, Ravesanker Ezhilarasan, Aram S Modrek, Melanie Graciani, Jerome Karp, Graysen McManus, Ananya Jambhale, Erik P Sulman.

Glioblastoma (GBM) patients have dismal survival due to resistance to initial ionizing radiation therapy (RT). Clonal evolution analysis reveals no dominant RT-resistant clones, prompting a genome-wide CRISPR screen to identify radiosensitizing targets. The screening highlights DNA damage response genes, validating the effectiveness of our approach. N-acylneuraminate-9-phosphatase (NANP), a critical enzyme in the sialic acid synthetic pathway, is top-ranked in the screening and associated with patient outcomes. After radiation, NANP-deficient cells exhibit more DNA damage, G2/M arrest and apoptosis, and impaired DNA repair by favoring non-homologous end-joining over homologous recombination. Mechanistically, NANP influences NF-κB signaling and the mesenchymal state by modulating sialylation and internalization of tumor necrosis factor receptor 1 (TNFR1), thereby affecting RT sensitivity. Intracranial orthotopic xenograft experiments validate the function of NANP in vivo. Here, we identify NANP as a radiosensitizing target dependent on TNFR1 sialylation and mesenchymal shift, providing a basis for developing RT sensitizers for GBM.

DOI: https://doi.org/10.1038/s41467-026-70853-x