bims-malgli 2026-02-15 papers

Issue of 2026–02–15
two papers selected by
Oltea Sampetrean, Keio University

Cell. 2026 Feb 11. pii: S0092-8674(25)01504-1. [Epub ahead of print]

Persistent T cell activation and cytotoxicity against glioblastoma following single oncolytic virus treatment in a clinical trial.

Maxime Meylan, Ye Tian, Lijian Wu, Alexander L Ling, Daniel Kovarsky, Graham L Barlow, Linh D Nguyen, Jason Pyrdol, Sascha Marx, Lucas Westphal, Julius Michel, L Nicolas Gonzalez Castro, Sydney Dumont, Andres Santos, Itay Tirosh, Mario L Suvà, E Antonio Chiocca, Kai W Wucherpfennig.

A recent first-in-human clinical trial demonstrated that survival in glioblastoma (GBM) patients following rQNestin34.5v.2 oncolytic virus treatment was associated with immune activation signatures. This study was registered at ClinicalTrials.gov (NCT03152318). Here, we provide in situ evidence of ongoing T cell-mediated cytotoxicity against tumor cells at late time points following single treatment, with deep and persistent T cell infiltration into tumor regions. Shorter distances between cleaved caspase-3+ tumor cells and granzyme B+ T cells were associated with longer progression-free survival following treatment. Pre-existing tumor-infiltrating T cells expanded locally upon treatment, correlating with longer overall patient survival. T cells with an early activation program closely interacted with tumor cells and were strongly enriched upon treatment. Viral remnants were restricted to necrotic regions, while T cells infiltrated deeply into live tumor regions. These data demonstrate that single oncolytic virus treatment can expand pre-existing T cell clones and trigger persistent T cell-mediated immunity against GBM.

Keywords: CODEX; GBM; T cell activation; T cell clonotype mapping; glioblastoma; oncolytic virus therapy; spatial transcriptomics; tissue-resident T cells; tumor microenvironment

DOI: https://doi.org/10.1016/j.cell.2025.12.055

bioRxiv. 2026 Feb 02. pii: 2026.01.30.702627. [Epub ahead of print]

IDH-mutant inhibitors enhance the sensitivity of IDH1-mutant gliomas to cysteine-methionine deprivation and ferroptosis.

Angeliki Mela, Abby Brand, Aayushi Mahajan, Athanassios Dovas, Nelson Humala, Smriti Kanangat, Allison C Kleinstein, Sandra Leskinen, Trang Tt Nguyen, Qiuqiang Gao, Pavan S Upadhyayula, Jia Guo, Brian Gill, Markus D Siegelin, Peter A Sims, Brent R Stockwell, Jeffrey N Bruce, Peter Canoll.

Cysteine is essential for synthesizing glutathione, the brain's main antioxidant, and cysteine deprivation can trigger ferroptosis. Here, using a new mouse model of IDH1-mutant glioma that recapitulates the characteristics of human IDH1-mutant low-grade gliomas, we demonstrate that IDH1-mutant glioma cells are significantly more vulnerable to cysteine deprivation alone or in combination with the ferroptosis inducer RSL3, compared to IDH1-wildtype glioma cells. In addition, treatments with the IDH-mutant inhibitors vorasidenib and ivosidenib further sensitize the cells to ferroptosis. Metabolomics analysis reveals that IDH1-mutant cells have altered cysteine and methionine metabolism with deficiency in transsulfuration, which is further exacerbated by cysteine-methionine deprivation and IDH-mutant inhibitors. Furthermore, dietary cysteine-methionine deprivation alone or in combination with convection-enhanced delivery of RSL3 or ivosidenib in vivo significantly prolongs survival of IDH1-mutant tumor-bearing mice. Our findings suggest that targeting cysteine and methionine metabolism in combination with IDH-mutant inhibition provides promising therapeutic strategies for IDH1-mutant gliomas.

DOI: https://doi.org/10.64898/2026.01.30.702627