bims-malgli 2026-05-03 papers

Issue of 2026–05–03
three papers selected by
Oltea Sampetrean, Keio University

Oncogene. 2026 Apr 29.

MS4A4A promotes macrophages M2 polarization via NF-κB /JAK-STAT6 axis, resulting GBM malignant progression.

Ziwei Li, Chunfa Wu, Zhongliang Cui, Bo Liang, Chen Wang, Mingchen Yu, Yishuo Sun, Di Wang, You Zhai, Changqing Pan, Jiazheng Zhang, Zhongfang Shi, Tao Jiang, Wei Zhang.

The immunosuppressive tumor microenvironment (TME) is a major issue in the malignant progression of glioma patients. The membrane spanning four domains A4A (MS4A4A) has a relationship with M2 polarization of macrophages, and participates in the malignant progression of various cancers. Therefore, exploration of the key role of MS4A4A contributing to glioma biological processes is urgently needed. We performed the bioinformatics analysis of M2 gene expression and built a model predicting the prognosis of glioma patients. Knocking down or overexpressing MS4A4A was achieved in macrophages, and we identified the polarization of macrophages with different MS4A4A expression levels. In vitro and in vivo experiments were used to investigate the role of MS4A4A in regulating M2 polarization and contributing to malignant behaviour in glioma. We found that MS4A4A was associated with the macrophages' M2 scores and the prognosis of GBM patients. MS4A4A had a higher expression level in M2 polarization macrophages. MS4A4A regulates macrophage M2 polarisation through NF-κB and JAK-STAT6 signalling pathways. Macrophages with MS4A4A overexpression promoted the proliferation, invasion, and TMZ-resistance of glioma cells in vitro and in vivo experiments. The treatment targeting the MS4A4A/ NF-κB/STAT6 axis could improve the prognosis and TMZ-resistance in the glioma mouse model. The present study revealed the novel mechanism of the MS4A4A regulating macrophages M2 polarization, contributing to the formation of immunosuppressive tumor microenvironment in glioma through NF-κB/STAT6 signaling pathways, which promotes the malignant biological process of glioma cells. Our results provided new evidence that NF-κB and STAT6 inhibitors might be a potential adjuvant agent in overcoming MS4A4A-mediated chemotherapy resistance in glioma.

DOI: https://doi.org/10.1038/s41388-026-03773-1

Neuro Oncol. 2026 Apr 30. pii: noag094. [Epub ahead of print]

5-ALA-mediated PpIX Accumulation in the Tumor Microenvironment of Glioma and its Implications for 5-ALA-based Local Tumor Therapies: A Review of the Literature.

Zeynep Özdemir, Marco Gallus, Michael Müther, Walter Stummer.

5-Aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) accumulation is widely used for fluorescence-guided surgery in malignant glioma. Beyond its diagnostic role, PpIX exhibits photo-, sono-, and radiosensitizing properties that enable locally applied tumor therapies. For these modalities, the cellular and subcellular localization of PpIX is a critical determinant of therapeutic efficacy, as it defines the site of reactive oxygen species generation and subsequent biological effects. In this comprehensive literature review, the cellular and subcellular distribution of 5-ALA-induced PpIX in gliomas and their tumor microenvironment (TME) was assessed. Studies were identified through a structured MEDLINE search and evaluated for evidence of PpIX localization in neoplastic and non-neoplastic cellular components. Accumulating data indicate that PpIX localizes not only within malignant glioma cells but also across multiple cellular components of the TME. Advanced imaging, single-cell, and spatial transcriptomic analyses demonstrate PpIX fluorescence frequently aligns with immunosuppressive myeloid populations and infiltrative tumor regions. Subcellularly, PpIX localizes in mitochondria, lysosomal-autophagic compartments, and extracellular structures, in a cell type dependent manner. These distribution patterns provide a biological basis for the immunomodulatory, anti-angiogenic, and cytotoxic effects observed in studies of 5-ALA-mediated local therapies. While macroscopic fluorescence remains clinically valuable for fluorescence-guided resection, the biologically relevant microscopic distribution of PpIX supports the concept that PpIX-based therapies may target not only tumor cells but also immunosuppressive and stromal compartments. A refined understanding of PpIX localization is therefore central to optimizing non-surgical 5-ALA-based therapies and their integration into multimodal glioma treatment paradigms.

Keywords: 5-ALA; Glioma; PpIX; TME

DOI: https://doi.org/10.1093/neuonc/noag094

bioRxiv. 2026 Apr 17. pii: 2026.04.14.715350. [Epub ahead of print]

KDM6 Enzymes are the Mechanistic Targets of Mutant IDH that Dictate Replication Stress Sensitivity.

Cancer-associated isocitrate dehydrogenase (IDH) mutations sensitize gliomas to replication stress, although the underlying mechanisms are unclear. IDH-mutant enzymes synthesize ( R )-2-hydroxyglutarate (R2HG), which broadly inhibits 2-oxoglutarate-dependent enzymes. We performed forward genetic screens targeting all 2-oxoglutarate-dependent enzymes and discovered that KDM6 histone demethylases play a vital role in protecting cells from replication stress. Genetic or R2HG-mediated repression of KDM6 catalytic activity sensitized glioma cells to disparate replication stress-inducing drugs, including Ataxia-telangiectasia and Rad3-related (ATR) and dihydroorotate dehydrogenase (DHODH) inhibitors. This liability is generalizable because KDM6A loss-of-function mutations commonly observed in urothelial carcinomas sensitized bladder cancer cells to DHODH inhibition, thereby phenocopying IDH mutations in glioma. To exploit these oncogene-induced replication stress vulnerabilities, we developed an effective, on-target, and well-tolerated DHODH inhibitor, GLIO-1, that is poised for clinical translation. Collectively, we reveal KDM6 activity as a fundamental determinant of replication stress sensitivity and nominate pan-cancer, mechanism-based biomarkers of ATR and DHODH inhibitor efficacy.
STATEMENT OF SIGNIFICANCE: We discovered that the KDM6 enzymes are the mechanistic targets of R2HG that mediate mutant IDH-induced replication stress hypersensitivity. We report a promising new DHODH inhibitor, GLIO-1, and nominate KDM6 and IDH mutations as predictive biomarkers for the antitumor effects of GLIO-1 and other replication stress inducers.

DOI: https://doi.org/10.64898/2026.04.14.715350