Immunotherapy for glioblastoma: current state, challenges, and future perspectives

Cellular and Molecular Immunology, Journal Year: 2024, Volume and Issue: 21(12), P. 1354 - 1375

Published: Oct. 15, 2024

Glioblastoma (GBM) is an aggressive and lethal type of brain tumor in human adults. The standard care offers minimal clinical benefit, most GBM patients experience recurrence after treatment. In recent years, significant advancements have been made the development novel immunotherapies or other therapeutic strategies that can overcome immunotherapy resistance many advanced cancers. However, benefit immune-based treatments limited because unique immune profiles, cell heterogeneity, immunosuppressive microenvironment. this review, we present a detailed overview current immunotherapeutic discuss challenges potential molecular mechanisms underlying GBM. Furthermore, provide in-depth discussion regarding GBM, which will likely require combination therapies.

Language: Английский

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Molecular principles underlying aggressive cancers

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 16, 2025

Language: Английский

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Spatial distribution of immune cells and their proximity to STING⁺ cells are associated with survival in glioblastoma

Clinical and Translational Medicine, Journal Year: 2025, Volume and Issue: 15(2)

Published: Jan. 24, 2025

Dear Editor, Glioblastoma (GBM), the most aggressive malignant tumour, is increasingly treated with immunotherapy.1-3 The stimulator of interferon genes (STING) pathway4 key to tumour immunity and a studied target for immunotherapy.5 This study explores immune landscape GBM, focusing on spatial relationships between tumour-associated cells (TAICs)6 STING-expressing cells, uncovering patterns linked prognosis. We 14 recurrent GBM patients using protein composition Gene Ontology (GO) analysis analyzed pathways in 69 newly diagnosed undergoing standard therapy. Spatial was performed QuPath, CytoMAP, R, as illustrated Figure 1A. From our proteomic analysis, we identified groups marked upregulation favourable responses. A total 99 proteins were highly upregulated group, while 170 more pronounced unfavourable group (Figure 1B). Clusters downregulated Benjamini-Hochberg False Discovery Rate. expression TMEM173, gene encoding STING, significantly elevated measured by mass spectrometer. results represented an abundance ratio, statistical significance confirmed adjusted p-value. 1C). GO showed that mainly response activation. 1D). Pathways such 'regulation innate response' 'phagocytic respiratory burst' strongly activation 1E). Additionally, like 'cell surface receptor signalling response', 'T cell migration' 'positive regulation T signalling' 1F). p-Values transformed -log10 significance, values above 1.3 considered significant. Table S1 provides categories associated used multiplex immunohistochemistry (IHC) analyze distribution markers TME. Markers included CD4+ (helper cells), CD8+ (cytotoxic CD11c+ (dendritic TCRγ/δ+ (γ/δ ATRX+ (tumour cells) DAPI+ (nuclei), STING primary marker interest. explored correlations populations IHC patient survival 2A). Tumour specimens stained immunofluorescence, pathologist selected regions interest (ROIs), which scanned at high magnification including ATRX, CD8, DAPI, CD4, CD11c TCRγ/δ. 2B). Multiplex enabled interactions microenvironment, quantifying its impact Correlation overall (OS) revealed significant positive correlation STING+ count OS (R = 0.256, p .036) 2C). No other statistically OS. Linear regression increase higher counts (β 0.481, 2D). S2 summarizes linear each When progression-free (PFS), increased improved 0.302, .025, R2 0.692) 2G). S3 details correlating OS, PFS. Comparing low only experienced recurrence 1.5 years after surgery 2E). Using coordinates phenotypes mapped R. Visualization without had number 2F). These show enables visual comparison TME differences outcomes. pathway affects modulating immunosuppressive immunoproliferative conditions through dendritic influencing progression based context.7 are present hematopoietic, endothelial, epithelial, fibroblast cells.8 endothelial play role promoting responses driven macrophages help recruitment across blood vessels.9 In brain's microvascular structure, comprises blood-brain barrier (BBB), type I interferons secreted enhance responses, impacting immunity.10 specifically targets STING+CD4−CD8−CD11c−ATRX−TCRγ/δ− likely forming BBB. mean distances from 3A). conducted unsupervised approach. method allowed us identify natural within data introducing potential biases predefined or labels. individuals poor outcomes generated positional plots surgical samples 3B). ROIs chosen further examined magnification, derived these plots. Voronoi diagrams merge clusters simplify representation Patients near few scarce Notably, close relationship prognosis, 3371 days, whereas 108 days. chord diagram link 3C). demonstrated negative distance -0.089, .047). Conversely, also 0.342, .042) 3D). shorter lower (p .047) 3E). Likewise, greater 3F). findings indicate association nearby patients. particular, closer proximity trend toward survival, appeared correlate better 3G). Given STING's dual roles promotion inhibition, may contribute shaping microenvironment nuanced manner. Hanwool Jeon: Conceptualization, methodology, formal curation, funding acquisition writing editing; Hayeong Kang: curation Jihyun Im: Validation, visualization, Suin Jo: Methodology, validation, Hyunchul Jung: Resources; Moinay Kim: Jae Hyun Jeong Hoon Chang-Ki Hong: Young-Hoon Sang Woo Song: Jinha Park: Methodology curation; Sang-Yeob supervision editing, Seungjoo Lee: investigation, resources, supervision, editing. thank Clinical Proteomics Core, Laboratory Animal Research ConveRgence mEDIcine research center (CREDIT) Asan Medical Center their equipment, services, expertise. authors declare no conflict supported grant Basic Science Program, funded Korean government's Ministry ICT (MSIT) (2022R1A2C2011941), Korea Health Technology R&D Project Industry Development Institute (KHID), & Welfare, Republic (grant number: RS-2024-00438911) Lee. support provided Fellowship Foundation (2022R1C1C2002698) Jeon. Please note: publisher not responsible content functionality any supporting information supplied authors. Any queries (other than missing content) should be directed corresponding author article.

Language: Английский

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A lupus-derived autoantibody that binds to intracellular RNA activates cGAS-mediated tumor immunity and can deliver RNA into cells

Science Signaling, Journal Year: 2025, Volume and Issue: 18(879)

Published: March 25, 2025

Nucleic acid–mediated signaling triggers an immune response that is believed to be central the pathophysiology of autoimmunity in systemic lupus erythematosus (SLE). Here, we found a cell-penetrating, SLE-associated antiguanosine autoantibody may present therapeutic opportunities for cancer treatment. The entered cells through nucleoside salvage-linked pathway membrane transit avoids endosomes and lysosomes bound endogenous RNA live cells. In orthotopic models glioblastoma, antibody localized areas adjacent necrotic tumor promoted animal survival manner depended on T Mechanistic studies revealed binding nucleic acids activated cytoplasmic pattern recognition receptor cyclic GMP-AMP synthase (cGAS), thereby stimulating cGAS-dependent cytotoxicity. Moreover, could carry deliver functional into tumor, brain, muscle tissues mice when administered locally. findings establish collaborative autoantibody–nucleic acid interaction translatable strategies nonviral gene delivery immunotherapy.

Language: Английский

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The STING Signaling: A Novel Target for Central Nervous System Diseases

Cellular and Molecular Neurobiology, Journal Year: 2025, Volume and Issue: 45(1)

Published: April 7, 2025

The canonical cyclic GMP-AMP (cGAMP) synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway has been widely recognized as a crucial mediator inflammation in many diseases, including tumors, infections, and tissue damage. STING signaling can also be activated cGAS- or cGAMP-independent manner, although the specific mechanisms remain unclear. In-depth studies on structural molecular biology have led to development therapeutic strategies involving modulators their targeted delivery. These may effectively penetrate blood-brain barrier (BBB) target multiple central nervous system (CNS) diseases humans. In this review, we outline both non-canonical pathways activation describe general associations between activity CNS diseases. Finally, discuss prospects for delivery clinical application agonists inhibitors, highlighting novel

Language: Английский

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2024 Lasker Award Recipient Zhijian Chen elucidates how DNA stimulates immunity

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 18, 2024

Language: Английский

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Unveiling the significance of cancer-testis antigens and their implications for immunotherapy in glioma

Discover Oncology, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 29, 2024

Language: Английский

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Immune Checkpoint Inhibitors in Glioblastoma IDHwt Treatment: A Systematic Review

Cancers, Journal Year: 2024, Volume and Issue: 16(24), P. 4148 - 4148

Published: Dec. 12, 2024

Purpose: A glioblastoma (GBM) is a primary brain tumor with significant unmet therapeutic needs. Immune checkpoint inhibitors (ICIs) have marked benefits in many different cancers but yet to show benefit for most GBM patients phase III trials. Methods: systematic review querying ClinicalTrials.gov prospective clinical trials investigating ICI between 1950 and July 2024 was performed. Search terms comprised 11 distinct ICIs. Data abstracted include trial NCT numbers study titles status, enrollment information, interventions, more. Clinical identifying outcomes were extracted. Results: One hundred seventeen identified; four 3. Most involved PD-1 or CTLA-4 blockade as monotherapy combination standard-of-care. The large, randomized included CHECKMATE 143, 498, 548, NRG BN007. These showed no improvement median overall survival progression-free unselected patients. Biomarker-directed analyses suggest that subset of may benefit. Conclusions: the treatment has not demonstrated clear evidence efficacy thus far. This serves quick reference results GBM. Biomarker-driven patient selection and/or novel approaches overcome resistance mechanisms remain areas viable inquiry.

Language: Английский

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