bims-malgli 2026-04-12 papers

bioRxiv. 2026 Apr 01. pii: 2025.08.06.668464. [Epub ahead of print]

Platelets regulate glioblastoma growth and immunity via sex-dependent PAR4 - Estrogen receptor beta signaling.

Sex differences in cancer outcome, including that of glioblastoma (GBM), are shaped by biological, hormonal, and immunological factors and impact disease progression, treatment responses, survival, and tumor microenvironment (TME) interactions. Platelets regulate the immune responses and tumor progression in many cancers, but it is not clear how they contribute to these sex-based differences by affecting the dynamics of the TME. Here, we show that GBM patients exhibit heightened platelet reactivity driven by PAR4 signaling. In murine GBM models, both pharmacological inhibition of PAR4 using BMS986120 and genetic deletion of PAR4 significantly prolong survival in females but not males. This survival advantage is estrogen dependent: it is preserved in chromosomal male-hormonal female mice within the four-core genotype model and is rescued in ovariectomized mice treated with estrogen. The survival benefit is TME specific and is mediated by platelet-driven enhancement of CD8⁺ T cell infiltration into the tumor. Inhibition of platelet PAR4 signaling increases calcium signaling through an estrogen-dependent interaction between PAR4 and estrogen receptor β (ERβ)-a receptor interaction not previously described. PAR4-activated platelets within the TME suppress CD8⁺ T cell function, and depletion of CD8⁺ T cells abolishes both the tumor-induced platelet reactivity and the survival benefit conferred by PAR4 inhibition. These findings establish platelet-mediated PAR4 signaling as a critical driver of tumor progression and identify sex-specific immune responses as key to therapeutic efficacy.

DOI: https://doi.org/10.1101/2025.08.06.668464

Sci Rep. 2026 Apr 05.

Identification of natural FGFR3 inhibitor for glioma using integrated computational and microRNA regulatory analysis.

Shehla Javaid, Nouman Ali, Samiah Shahid, Muhamamd Nouman Majeed.

Keywords: FGFR3; Glioblastoma; Guggulsterone; Molecular docking; Molecular dynamics simulation; Natural inhibitor

DOI: https://doi.org/10.1038/s41598-026-45845-y

Nat Commun. 2026 Apr 08. pii: 3405. [Epub ahead of print]17(1):

L-RNA aptamer-based CXCL12 inhibition combined with radiotherapy and bevacizumab in newly-diagnosed glioblastoma: expansion of the phase I/II GLORIA trial.

Rapid vascular recovery is a key feature preceding glioblastoma (GBM) recurrence after radiotherapy (RT). We performed spatial expression analyses, providing a rationale for dual inhibition of two non-redundant, spatially distinct acting factors, CXCL12 and VEGF. Subsequently, we expanded a multicentric phase 1/2 trial (NCT04121455), which initially combined RT and the CXCL12-neutralizing L-RNA-aptamer olaptesed pegol (NOX-A12) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT promoter methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose, recommended phase 2 dose, NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life, median progression-free survival (PFS), 6-months PFS and overall survival (OS). For the expansion arm, six patients were included that additionally received the VEGF-targeting antibody bevacizumab (BEV) to RT and NOX-A12. Combinatory treatment was well-tolerated and safe with no treatment-related deaths, resulting in abrogated tumor perfusion (rCBV, FTBhigh) and delayed tumor regrowth as per mRANO. Median progression-free (PFS) and overall survival (OS) after RT + BEV + NOX-A12 were 9.1 and 19.9 months, respectively, significantly outperforming RT + NOX-A12 (p = 0.009; p = 0.021) in a post-hoc comparative analysis, with two patients exceeding 2-year OS. These findings establish proof-of-principle for dual inhibition of CXCL12 and VEGF in patients with newly-diagnosed GBM following RT.

DOI: https://doi.org/10.1038/s41467-026-71362-7

iScience. 2026 Apr 17. 29(4): 115361

Glioblastoma invasion into different organoid hosts reveals cell-intrinsic and proliferative migratory programs.

Christopher Y Akhunbay-Fudge, Bronwyn K Irving, Alima Ismail, Sabrina Samuel, Emma Smedley, Holly E Bradford, Steven Bagley, Alexander Baker, Iain M Hagan, Deena M A Gendoo, Kevin Critchley, Ryan K Mathew, Heiko Wurdak.

Akhunbay-Fudge et al. develop two complementary single-cell profiling methods to determine glioblastoma (GB) invasion phenotypes, focusing on the influence of host organoid developmental lineage (neural versus endodermal) and cell cycle progression on GB invasion within tumor assembloids. Notably, GB cells invaded both neural and endodermal organoid hosts, whereas non-malignant adult brain cells lacked this capacity. Single-cell mRNA sequencing revealed gene expression changes in invading tumor cells and surrounding environmental assembloid cells. Concurrently, the "DyPheT" automated tracking tool enabled real-time correlation of cell cycle phases with malignant cell migration within cerebral organoids, which can be utilized for treatment response assessment, exemplified by the investigational compound RP-6306. Collectively, these approaches identify an intrinsic (cell autonomous) gene expression signature linked to GB invasion and support a "go-and-grow" paradigm by revealing a highly migratory (and RP-6306-refractory) GB subpopulation active in the G2/M phase of cell cycle.

Keywords: Cancer; Cell biology

DOI: https://doi.org/10.1016/j.isci.2026.115361

Neuro Oncol. 2026 Apr 03. pii: noag075. [Epub ahead of print]

Enhancing Immune Cell Trafficking to Brain Tumors: Recent Advances and Therapeutic Strategies.

Zhuoqi Tong, Chulyong Kim, James L Ross, Costas Arvanitis.

For peripheral immune cells to be effective against brain tumors require multiple coordinated steps, including migration and homing to the local microenvironment-collectively referred to as immune cell trafficking-followed by survival, proliferation, and persistence, all while remaining functional. This review focuses on the often-overlooked first step, trafficking, which is critical for initiating subsequent processes and driving antitumor responses. We summarize the migration cascade of immune cells, including T cells and macrophages, across the blood-brain barrier (BBB), and how primary brain tumors as well as brain metastases alter the molecular pathways and interactions associated with immune cell migration cascade across the BBB and their functional homing. Subsequently, we highlight recent developments in engineering biomolecular, cellular, and physical methods to modulate the tumor microenvironment and improve the functional trafficking of immune cells in brain tumors. Our analysis reveals novel combinations to potentiate antitumor responses via feedforward mechanisms and modular therapeutic strategies designed to improve the migration and accumulation of functional immune cells in brain tumors. A deeper understanding of immune cell trafficking, distribution, and homing through the application of pre-clinical and clinical imaging techniques along with the development of in vitro/ex vivo platforms, should enable new and more potent immunotherapy strategies against primary brain malignancies and brain metastases as well as accelerate their translation to the clinics.

Keywords: cell trafficking; glioblastoma; immunotherapy; tumor microenvironment

DOI: https://doi.org/10.1093/neuonc/noag075