bims-spamet 2026-06-28 papers

Int Rev Immunol. 2026 Jun 27. 1-18

Metabolic alterations in the tumor microenvironment influence the anti-tumor immune function of CD8+ T cells via epigenetic modifications.

Yaru Liu, Wei Du, Weimin Deng.

Metabolic reprogramming within the tumor microenvironment (TME) is a pivotal driver of CD8+ T cell dysfunction in cancer. Tumor cells outcompete T cells for essential nutrients, including glucose and amino acids, while accumulating immunosuppressive metabolites such as lactate and 2-hydroxyglutarate. Beyond direct functional impairment, emerging research reveals that these metabolic alterations orchestrate CD8+ T cell transcriptional programs by remodeling their epigenome-via histone modifications, DNA methylation, and non-coding RNA networks-thereby dictating their differentiation, cytotoxic potential, and memory formation. A deeper understanding of how TME-derived metabolic signals shape the epigenetic landscape of CD8+ T cells is crucial for improving current cancer immunotherapeutic strategies. This review systematically delineates how key TME metabolic features, including nutrient deprivation and oncometabolite accumulation, regulate CD8+ T cell fate through epigenetic pathways. Furthermore, we discuss promising therapeutic strategies that target the metabolism-epigenetics axis to reinvigorate CD8+ T cell anti-tumor immunity, offering novel perspectives for enhancing adoptive cell therapy and immune checkpoint blockade.

Keywords: CD8+ T cells; Cancer immunotherapy; epigenetics; metabolic reprogramming; tumor microenvironment

DOI: https://doi.org/10.1080/08830185.2026.2687543

Front Immunol. 2026 ;17 1837084

Cytotoxic lymphocyte heterogeneity in glioblastoma: insights from single-cell and spatial multiomics toward precision immunotherapeutic reprogramming.

Wentao Dong, Yang Li, Zhuolin Wu, Quanlin Fu, Jinshuang Zhao, Bangyue Wang, Jia Yao, Chenglu Lu, Minfeng Tong.

Glioblastoma (GBM) represents the most aggressive primary brain tumor in adults, characterized by a profoundly immunosuppressive tumor microenvironment (TME) that systematically disables cytotoxic lymphocyte function and renders conventional immunotherapy largely ineffective. While exhaustion of CD8+ T cells and natural killer (NK) cells within solid tumors has been extensively studied in other cancer types, the CNS-specific architectural, metabolic, and molecular constraints that shape cytotoxic lymphocyte heterogeneity in GBM remain insufficiently characterized. Recent advances in single-cell RNA sequencing (scRNA-seq) and spatial multiomics have begun to reveal a rich landscape of cytotoxic lymphocyte subpopulations in GBM. These include TCF-1+ progenitor-exhausted T cells (Tpex), terminally exhausted CD8+ T cells (Tex), and dysfunctional natural killer (NK) cell subsets, each distributed across anatomically distinct immune niches. This review synthesizes current knowledge across three interconnected areas: the single-cell atlas of GBM-infiltrating cytotoxic lymphocytes; the spatial organization of their dysfunction within perinecrotic, perivascular, and infiltrative-edge niches; and the epigenetic and transcriptional programs that underlie GBM-specific cytotoxic failure, including dysregulation of the TOX/TCF-1 axis and IDH-mutation-driven silencing of NKG2D ligands. Critically, we compare CD8+ T cell and NK cell exhaustion mechanisms, highlighting their mechanistic divergence and therapeutic implications. We further discuss how these multiomics insights can be translated into neurosurgically relevant strategies, including intraoperative tumor profiling, progenitor T cell expansion via epigenetic priming, NKG2A/TIGIT dual blockade, and intracavitary delivery of engineered NK cells. Together, this review proposes a spatially and cellularly resolved framework for understanding cytotoxic immune failure in GBM and outlines precision immunotherapy approaches tailored to the unique immunobiology of the CNS tumor microenvironment.

Keywords: NK cell dysfunction; blood-brain barrier; cytotoxic lymphocytes; glioblastoma; immunotherapy; progenitor exhausted T cells; single-cell transcriptomics; spatial genomics

DOI: https://doi.org/10.3389/fimmu.2026.1837084

J Exp Med. 2026 Aug 03. pii: e20252115. [Epub ahead of print]223(8):

The transcription factor IRF8 drives tumor-specific exhaustion in CD8+ T cells.

Marco Ongaro, Romane Thouenon, Isaac Crespo, Alexandre Dumez, Mélanie Charmoy, Eduardo Roman Camacho, Victoria J Morel, Daniela Cropp, Emma Desponds, Giulio Zanette, Yi-Chuan Wang, Letizia Vergili, Laure Tillé, Inés Di Resta, Marine M Leblond, Jésus Corria Osorio, Ping-Chih Ho, Werner Held, Grégory Verdeil.

T cell exhaustion is a major obstacle to effective immunotherapy in cancer and chronic infection. Here, we identify the transcription factor IRF8 as a tumor-specific regulator of CD8+ T cell exhaustion. IRF8 is strongly expressed in tumor-reactive CD8+ T cells but not during chronic viral infection. Its expression is induced by TCR signaling and can be suppressed by type I IFN (IFN-I). Sustained IFN-I signaling, a hallmark of chronic infection, correlates with reduced chromatin accessibility at the Irf8 locus and progressive repression of Irf8 expression. In tumor-specific CD8+ T cells, IRF8 overexpression enhanced TOX expression while reducing IFNγ, granzyme B, and TNF production. Conversely, Irf8 deficiency diminished exhaustion, restored effector functions, and improved tumor control. Mechanistically, IRF8 directly binds the Tox locus and promotes its transcription. We further show that additional IRF-family transcription factors contribute similarly to the exhausted T cell program, identifying this transcriptional network as a key regulator of tumor-associated T cell dysfunction.

DOI: https://doi.org/10.1084/jem.20252115