bims-malgli 2025-07-20 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2025–07–20
ten papers selected by
Oltea Sampetrean, Keio University

In vivo generation of CAR macrophages via the enucleated mesenchymal stem cell delivery system for glioblastoma therapy.
Lipid nanoparticle formulation for gene editing and RNA-based therapies for glioblastoma.
TIGIT expression dictates the immunosuppressive reprogramming of myeloid cells in glioblastoma.
Treatment Resistant Persister Cells Exploit Macrophage Lipid Metabolism to Sustain Glioblastoma Growth.
Oncostreams organize peritumoral glioma infiltration.
Multicellular model of temozolomide resistance in glioblastoma reveals phenotypic shifts in drug response and migratory potential.
Cytomegalovirus-induced oncomodulation drives immune escape in glioblastoma.
High-Throughput Targeted Drug Screening for NF1-associated High-Grade Gliomas with ATRX Deficiency.
Enhanced lipid metabolism serves as a metabolic vulnerability to a polyunsaturated fatty acid (PUFA)-rich diet in glioblastoma.
Steroid receptor coactivator-1 facilitates METTL3-mediated m6A modification by coactivating NF-κB and promotes the malignant progression of glioblastoma.

Proc Natl Acad Sci U S A. 2025 Jul 22. 122(29): e2426724122

In vivo generation of CAR macrophages via the enucleated mesenchymal stem cell delivery system for glioblastoma therapy.

Lei Zhou, Qingying Song, Xin Zhang, Mengnian Cao, Dayu Xue, Yiwen Sun, Meihua Mao, Xinling Li, Zhenzhong Zhang, Junjie Liu, Jinjin Shi.

  Glioblastoma multiforme (GBM) is one of the most aggressive intracranial tumors for which there is no effective treatment. Chimeric antigen receptor macrophage (CAR-M) therapies have demonstrated impressive therapeutic efficacy in solid tumors; however, the cost and rigor associated with manufacturing engineered macrophages ex vivo can be prohibitive. Here, we utilized enucleated mesenchymal stem cells (MSCs) as vehicles for the targeted delivery of CAR-encoding plasmid to reprogram glioma-associated microglia/macrophages (GAM), thereby achieving CAR-M preparation in vivo. Specifically, we observed that the enucleated cells retained the key organelle function and membrane integrity, and actively homed to glioma tissue. Interestingly, enucleated MSCs underwent intrinsic apoptosis due to the absence of the nucleus, which subsequently triggered macrophage-specific endocytosis, thereby achieving precise delivery of CAR-plasmids to GAM. Compared with lipid nanoparticles, this strategy specifically generated sufficient numbers of CAR-M in glioma situ to achieve GBM therapy. Moreover, this process altered the immune cell profiles within the tumor by increasing cytotoxic T cells and M1-like macrophages with antitumor activity. When combined with CD47-blocking therapies, tumor growth was completely suppressed in the GBM orthotopic mouse model, resulting in a 90-d survival rate of 83%. Collectively, our strategy provides a viable platform technology for CAR-M generation in vivo, which is expected to provide an approach for GBM therapy.

Keywords:  CAR macrophages; enucleated cells delivery systems; glioblastoma; macrophage targeting

DOI:  https://doi.org/10.1073/pnas.2426724122
Neuro Oncol. 2025 Jul 11. pii: noaf162. [Epub ahead of print]

Lipid nanoparticle formulation for gene editing and RNA-based therapies for glioblastoma.

Yanhong Zhang, Rosalia Rabinovsky, Evgeny Deforzh, Ami Kobayashi, Anastasia Kuzkina, Johnna Francis Varghese, Damita Rai, Joanna A Korecka, Vikram Khurana, Gopal Murugaiyan, David Morrissey, Erik J Uhlmann, Anna M Krichevsky.

   BACKGROUND: Glioblastoma (GBM), one of the deadliest cancers, resists current therapies, with drug development hindered by its high heterogeneity. However, GBM consistently relies on microRNA-10b (miR-10b), a key driver of glioma growth and a promising therapeutic target. miR-10b gene editing represents a potential treatment, but effective delivery strategies for gene editing systems in GBM remain unexplored.
METHODS: We developed lipid nanoparticles (LNPs) encapsulating Cas9 mRNA and a miR-10b-targeting sgRNA (termed miRTEN). miRTEN was tested in glioma stem cells (GSCs) and orthotopic GBM models to assess therapeutic efficacy, immune responses, and safety.
RESULTS: Intracerebroventricular (ICV) injections of miRTEN enabled broad and durable Cas9 mRNA expression and miR-10b gene editing in tumor core and invasive areas across diverse GBM models. miRTEN significantly suppressed tumor growth, reduced GSC proliferation and viability, with therapeutic outcomes correlating with dose-dependent miR-10b suppression. Combining miRTEN with temozolomide (TMZ) further enhanced tumor suppression, overcoming TMZ resistance and improving survival. In immunocompetent models, miRTEN activated anti-tumor immune responses, increased cytotoxic CD8+ T cells infiltration, and promoted durable immune memory, enabling tumor rejection upon rechallenge. Safety assessments demonstrated that miRTEN selectively targets GBM cells, sparing normal brain tissues and causing no significant off-target toxicity.
CONCLUSION: As in vivo CRISPR-based drugs advance toward clinical applications, our findings demonstrate the potential of LNPs-mediated CRISPR-Cas9 systems for targeted miR-10b editing and, more generally, gene editing and RNA therapies for GBM. miRTEN monotherapy, as well as its combination with standard care, offers a promising, safe, and effective approach to improving outcomes in GBM.

Keywords:  CRISPR-Cas9; Glioblastoma; gene editing; lipid nanoparticles; microRNA-10b

DOI:  https://doi.org/10.1093/neuonc/noaf162
bioRxiv. 2025 May 02. pii: 2025.04.24.648993. [Epub ahead of print]

TIGIT expression dictates the immunosuppressive reprogramming of myeloid cells in glioblastoma.

Mohammad Asad, Julio Inocencio, Stefan Mitrasinovic, Minori Aoki, Celina Crisman, Patrick Lasala, Emad Eskandar, Chandan Guha, XingXing Zang, Ian F Parney, Benjamin T Himes.

Glioblastoma (GBM) is a deadly brain cancer with near-universal recurrence despite maximal treatment for which new innovations are sorely needed. Immunotherapy has yet to make significant gains in GBM treatment despite revolutionizing other cancer therapies, due in part to GBM-mediated immune suppression. This immune derangement proceeds through several mechanisms, but increasing evidence points to critical roles for tumor-derived extracellular vesicles (EVs) and immunosuppressive myeloid cells as key factors in this process. In the present study, we demonstrate broad expression of TIGIT across myeloid cell populations in the GBM microenvironment, a finding recapitulated by conditioning healthy monocytes with GBM-derived EVs. Further, knockdown of TIGIT expression reduced the immunosuppressive polarization of monocytes, resulting in improvement in T cell function. This finding proceeded in an NLRP3-dependent manner, with substantial co-localization of TIGIT and NLRP3 expression prior to knockdown. These findings point to a novel role for TIGIT expression in diverse myeloid cells in the GBM microenvironment as a marker of immunosuppressive activity and further indicate a hierarchy of immunomodulatory protein activity in these myeloid cells, with TIGIT knockdown unmasking the pro-inflammatory activity of NLRP3. This study bolsters understanding of the immunosuppressive complexities of myeloid cells in the GBM microenvironment, while lending further support to prevention or attenuation of immunosuppressive myeloid cell activity as a means of restoring immune function in GBM.
Graphical abstract: (Created in BioRender. Asad, M. (2025) https://BioRender.com/euiljoq.
Key Points: Tumor-mediated immune suppression is a key barrier to the development of effective immunotherapies for GBM.TIGIT is broadly expressed in myeloid cells within the GBM microenvironment and can be induced by GBM-derived extracellular vesicles.Knockdown of TIGIT reduces immunosuppressive polarization of monocytes and enhances T cell activity via NLRP3 signaling, implicating TIGIT expression as a targetable modifier of immunosuppressive activity in GBM-associated myeloid cells.
Importance of the Study: Glioblastoma (GBM) remains a formidable clinical challenge, with poor prognosis and limited response to current immunotherapies. This study uncovers a novel immunosuppressive axis involving TIGIT expression in myeloid cells, which are key players in the GBM tumor microenvironment. By demonstrating GBM-derived extracellular vesicles induce TIGIT in healthy monocytes and TIGIT knockdown diminishes immunosuppressive polarization in an NLRP3-dependent manner, this study highlights TIGIT as both a marker and modulator of immune dysfunction in GBM. These findings introduce a functional hierarchy of immunoregulatory proteins in tumor-associated myeloid cells, positioning TIGIT as a potential checkpoint target. Restoring immune activity by disrupting this axis could enhance the efficacy of immunotherapy in GBM. Thus, this research not only advances our understanding of tumor-induced immune suppression but also opens a promising therapeutic avenue to reinvigorate anti-tumor immunity in a cancer type historically resistant to immunotherapeutic approaches.

DOI: https://doi.org/10.1101/2025.04.24.648993
bioRxiv. 2025 Jun 10. pii: 2025.06.07.658345. [Epub ahead of print]

Treatment Resistant Persister Cells Exploit Macrophage Lipid Metabolism to Sustain Glioblastoma Growth.

Avirup Chakraborty, Changlin Yang, Aryeh Silver, Diana Feier, Guimei Tian, Avinash Pittu, Christina Von Roemeling, Nagheme Thomas, Michael Andrews, Cole Conforti, Olusegun O Sobanjo, Nyla T Searl, Miruna N Anica, Raquel McTiernan, Maryam Rahman, Jianping Huang, Jeffrey K Harrison, Duane A Mitchell, Matthew Sarkisian, Loic P Deleyrolle.

Glioblastoma (GBM) displays pronounced intratumoral heterogeneity, posing significant challenges to understanding its biology and developing effective treatments. Using spatial multi-omics, in vivo functional assays, and systems-level analysis, we delineate the diverse metabolic and immune architecture of GBM. We identify a lipid-dependent lineage of treatment-resistant persister cells (TRPCs) that engage tumor-associated macrophages (TAMs) in a spatially organized, metabolically specialized crosstalk. TRPCs co-opt CCR2⁺, CSF1R⁺, CD163 + TAMs for lipid scavenging and acquisition, promoting a pro-tumorigenic and immunosuppressive microenvironment. This cooperative axis is critically dependent on lipid chaperones like FABPs, whose targeting disrupts TAM recruitment, remodels immune composition, and suppresses tumor growth. Retrospective clinical analyses reveal that elevated TRPC-associated transcriptome may serve as stratification criteria to identify patients benefiting from lipid-lowering therapies like statins. Our findings uncover a targetable immunometabolic circuit between TRPCs and TAMs and support the development of precision therapies that disrupt lipid-fueled tumor-immune cooperation in GBM.
In brief: Treatment-resistant persister cells (TRPCs) in glioblastoma spatially engage TAMs to facilitate lipid transfer, thereby sustaining tumor growth and promoting immune evasion. Targeting this TRPC-TAM metabolic axis reprograms the immunosuppressive microenvironment and improves therapeutic outcomes, revealing a clinically actionable metabolic vulnerability with potential for precision immune-metabolic interventions in GBM.
Highlights: GBM exhibits spatially resolved heterogeneity revealing correlative metabolic and immune micro-nichesTRPC lineage promotes a pro-tumorigenic and immunosuppressive microenvironment by recruiting lipid-specialized TAMsTRPC lineage hijacks TAMs for metabolic support via stimulating lipid transfer and acquisitionDisruption of the TRPC-TAM lipid axis, including through FABP3 targeting, reprograms the immune landscape, limits TAM recruitment, and impairs tumor progressionTRPC lineage and associated micro-niche transcriptomic profiles can serve as criteria for patient stratification and identification of responders to lipid-lowering therapies, such as statins.

DOI: https://doi.org/10.1101/2025.06.07.658345
Nat Cancer. 2025 Jul 15.

Oncostreams organize peritumoral glioma infiltration.

Pedro R Lowenstein.

DOI: https://doi.org/10.1038/s43018-025-01022-0
bioRxiv. 2025 Jul 11. pii: 2025.07.08.663674. [Epub ahead of print]

Multicellular model of temozolomide resistance in glioblastoma reveals phenotypic shifts in drug response and migratory potential.

Victoria A Kriuchkovskaia, Ela K Eames, Sydney A McKee, Paul J Hergenrother, Rebecca B Riggins, Brendan A C Harley.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, with limited survival outcomes due to tumor recurrence, mainly driven by GBM cell invasion and therapy resistance. Although temozolomide (TMZ) remains the standard-of-care chemotherapeutic, its long-term efficacy is often compromised by rapid emergence of acquired resistance, largely mediated by the DNA repair enzyme, methylguanine methyltransferase (MGMT). To investigate the interplay between tumor heterogeneity, drug resistance, and the extracellular matrix (ECM) microenvironment, we adapted a 3D methacrylamide-functionalized gelatin (GelMA) hydrogel model to study the behavior of mixed populations of TMZ-sensitive and TMZ-resistant GBM cells. Using both single-cell distributions and multicellular spheroids, we report the impact of heterogeneous cell populations and TMZ dosing regimens, including physiological, supraphysiological, and metronomic TMZ schedules, on drug response and migration. We show that the combination therapy of TMZ with an MGMT inhibitor, lomeguatrib, can modulate TMZ resistance in vitro. This hydrogel model enables systematic investigation of GBM heterogeneity, go-or-grow phenotypic plasticity, and therapeutic resistance in an ECM-rich microenvironment, offering a valuable platform for future translational research.

DOI: https://doi.org/10.1101/2025.07.08.663674
Sci Rep. 2025 Jul 17. 15(1): 25981

Cytomegalovirus-induced oncomodulation drives immune escape in glioblastoma.

Harald Krenzlin, Felix Corr, Deepak Ailani, Philipp Einheuser, Thomas Bukur, Thomas Rößler, Alina Henrich, Raja Hollnagel, Alice Dauth, Libo Hu, Leon Schmidt, Marion Griessl, Michael Gutknecht, Noe Mercado, Beat Alessandri, Charles H Cook, Florian Ringel, Sean E Lawler, Niels A Lemmermann, Naureen Keric.

  Immune evasion and suppression lead to unchecked tumor growth in glioblastoma. Cytomegalovirus (CMV) has been implicated in tumor progression and modulation in glioblastoma. To investigate this potential connection, CMV-associated changes in the glioblastoma immune landscape were characterized in vitro and in a murine glioblastoma model. Infection of mouse glioblastoma cells (GL261Luc2) with mCMV resulted in a short period of viral replication. MHC-I cell surface expression was reduced after mCMV infection by approximately 40% compared with non-infected tumor cells (p < 0.0001). Viral regulators of antigen presentation (vRAP) were shown to be responsible for MHC-I downregulation using a recombinant mCMV (ΔvRAP) lacking the known immune evasion genes. RNA sequencing of mCMV infected GL261Luc cells revealed 2711 differentially expressed genes (p < 0.005). Of particular interest was the downregulation of MHC-I-associated genes H2-Q1-10 and Tap1 fter CMV infection. In vivo, the mCMV immediate early gene (IE1) was detected in brains of mCMV + animals after tumor implantation and increased during tumor growth. mCMV + mice had significantly shorter survival than controls, depending on initial tumor size (P < 0.001). Tumor immune infiltrates in mCMV infection were characterized by B cell infiltrates and low levels of NK cell infiltration. Here, the landscape of immune cell infiltrates is shifted toward B cell infiltration and reduced numbers of NK cells. CMV leads to immune evasion mediated MHC-I downregulation in murine glioblastoma. Thus, CMV infection in glioblastoma may contribute to unchecked tumor growth in glioblastoma by increasing immune evasion.

Keywords:  CMV mouse model; Cytomegalovirus; Glioblastoma; Immune evasion; MHC I

DOI:  https://doi.org/10.1038/s41598-025-10107-w
bioRxiv. 2025 Jun 11. pii: 2024.12.14.628525. [Epub ahead of print]

High-Throughput Targeted Drug Screening for NF1-associated High-Grade Gliomas with ATRX Deficiency.

Swati Dubey, Simran Rai, Fabiola Guillen, Ajeeth Iyer, Su Aung, Ming Yuan, Charles G Eberhart, Fausto J Rodriguez.

Neurofibromatosis type 1 (NF1)-associated high-grade gliomas (HGGs) harboring ATRX mutations exhibit an aggressive clinical phenotype, driven by heightened genomic instability and metabolic reprogramming. Existing therapies, including chemotherapy and radiotherapy, are limited by resistance mechanisms and formation of secondary malignancy, underscoring the need for novel therapeutic strategies. Here, we report the results of a high-throughput screening of 10,000 small molecules aimed at identifying compounds selectively targeting vulnerabilities associated with concurrent ATRX and NF1 loss. Among the screened compounds, K784-6195 (ChemDiv ID) emerged as a promising candidate, exhibiting marked selective cytotoxicity in NF1-associated glioma cell lines with ATRX deficiency (IC50 = 4.84 µM). In comparison, wild-type ATRX sporadic glioma cell lines (U251) exhibited significantly reduced sensitivity to K784-6195 (IC50 = 37.03 µM). However, ATRX knockout U251 glioma cells recapitulating concurrent ATRX and NF1 loss exhibited heightened susceptibility to K784-6195 (IC50 = 20-23 µM) compared to their wild-type counterpart. Metabolomic analysis revealed that K784-6195 treatment impairs metabolic pathways, including the pentose phosphate pathway, glutamine metabolism, and redox homeostasis, leading to oxidative stress and impaired cell survival. These findings highlight K784-6195 as a promising candidate for therapeutic development, offering a targeted approach for the treatment of NF-1 associated HGGs with ATRX deficiency.

DOI: https://doi.org/10.1101/2024.12.14.628525
Res Sq. 2025 Jun 24. pii: rs.3.rs-6355361. [Epub ahead of print]

Enhanced lipid metabolism serves as a metabolic vulnerability to a polyunsaturated fatty acid (PUFA)-rich diet in glioblastoma.

Prakash Chinnaiyan, Shiva Kant, Yi Zhao, Pravin Kesarwani, Kumari Alka, Jacob Oyeniyi, Ghulam Mohammad, Nadia Ashrafi, Stewart Graham, C Ryan Miller.

Enhanced lipid metabolism, which involves the active import, storage, and utilization of fatty acids from the tumor microenvironment, plays a contributory role in malignant glioma transformation; thereby, serving as an important gain of function. In this work, through studies initially designed to understand and reconcile possible mechanisms underlying the anti-tumor activity of a high-fat ketogenic diet, we discovered that this phenotype of enhanced lipid metabolism observed in glioblastoma may also serve as a metabolic vulnerability to diet modification. Specifically, exogenous polyunsaturated fatty acids (PUFA) demonstrate the unique ability of short-circuiting lipid homeostasis in glioblastoma cells. This leads to lipolysis-mediated lipid droplet breakdown, an accumulation of intracellular free fatty acids, and lipid peroxidation-mediated cytotoxicity, which was potentiated when combined with radiation therapy. Leveraging this data, we formulated a PUFA-rich modified diet that does not require carbohydrate restriction, which would likely improve long-term adherence when compared to a ketogenic diet. The modified PUFA-rich diet demonstrated both anti-tumor activity and potent synergy when combined with radiation therapy in mouse glioblastoma models. Collectively, this work offers both a mechanistic understanding and novel approach of targeting this metabolic phenotype in glioblastoma through diet modification and/or nutritional supplementation that may be readily translated into clinical application.

DOI: https://doi.org/10.21203/rs.3.rs-6355361/v1
Oncogene. 2025 Jul 15.

Steroid receptor coactivator-1 facilitates METTL3-mediated m6A modification by coactivating NF-κB and promotes the malignant progression of glioblastoma.

Liang Liu, Rui Wang, Ke Cheng, Chunmei Bai, Yuke Ji, Yifei Zhang, Haoran Yang, Miaomiao Gong, Fang Xie, Yongshun Zhao, Jinjin Pan, Yuhui Yuan.

Glioblastoma (GBM) is an incurable disease with a poor prognosis. However, the potential impact of steroid receptor coactivator-1 (SRC-1) on N6-methyladenosine (m6A) RNA modification and its role in promoting malignant progression in GBM remain unclear. The relationship between SRC-1 and the m6A "writer" protein, methyltransferase 3 (METTL3), was analyzed using data from the CGGA database. Dot blot and MeRIP‒qPCR were performed to evaluate the effects of SRC-1 knockdown or overexpression on the level of m6A modification in GBM. The biological functions of SRC-1 in regulating METTL3 in GBM were evaluated by assessing its effects on proliferation, migration, cell cycle, colony formation, and apoptosis in vitro and the tumor volume/weight of nude mice xenografted with GBM cells in vivo. Co-IP, immunofluorescence, dual-luciferase, and ChIP‒qPCR assays were subsequently conducted. By analyzing the CGGA database, we determined that SRC-1 has a close positive relationship with METTL3 in GBM. SRC-1 significantly increased the m6A RNA modification level in GBM, SRC-1 knockdown markedly inhibited c-Myc m6A methylation and mRNA stability by suppressing METTL3, and SRC-1 overexpression led to hypermethylation by increasing METTL3. SRC-1 knockdown inhibited the proliferation, migration, apoptosis resistance, and S and G2/M phases of GBM cells in vitro. Mechanically, SRC-1 interacted with the heterodimer of NF-κB p50/p65, whereby p65 activated METTL3 by directly binding to a specific region of its promoter (+18 to +27 bp), thereby increasing the m6A modification of c-Myc and ultimately promoting GBM progression. Importantly, both SRC-1 knockdown and treatment with bufalin, an SRC inhibitor, reduced GBM progression. In conclusion, this study provides the first comprehensive evidence that SRC-1 facilitates GBM progression by binding to NF-κB and regulating METTL3-mediated m6A modification of c-Myc, offering new insights into potential therapeutic strategies for GBM. Schematic diagram of the mechanism revealed in this research. SRC-1 regulates METTL3-mediated m6A RNA modification of c-Myc to promote GBM progression by binding to the NF-κB transcription factor. Created in BioRender. https://BioRender.com .

DOI: https://doi.org/10.1038/s41388-025-03494-x