Authors
Congcong Li, Qian Wang, Qitai Zhao, Qianfeng Cai, Siyang Wang, Yu Ping, Xuan Zhao, Xinfeng Chen, Chunyi Shen, Haiming Qin, Guohui Qin, Jiqi Shan, Zhen Zhang, Yi Zhang
Published in
Cancer immunology research. Aug 11, 2026. Epub Aug 11, 2026.
Abstract
Chimeric antigen receptor (CAR)-T cell exhaustion constitutes a critical barrier to sustained antitumor efficacy. Through transcriptomic analysis of CAR-T cells from patients with lymphoma, we identified the histone variant macroH2A2 (H2AFY2) as a critical regulator of T cell exhaustion-a finding consistently observed across multiple tumor models. In mice, T cell-specific knockout of H2afy2 promots the expression of inhibitory receptors by activating the nuclear factor kappa-B pathway and increasing chromatin accessibility at the Rela locus, as demonstrated by single-cell RNA-sequencing and assay for transposase-accessible chromatin sequencing. H2AFY2 overexpression in CD8+ T cells induces prominent epigenetic remodeling, characterized by increased H3K27me3 enrichment. Mechanistically, H3K27me3 enrichment at the Rela locus suppresses p65-mediated transcriptional activation, leading to downregulation of the exhaustion-associated transcription factor TOX and consequent amelioration of T cell exhaustion. Furthermore, H2AFY2-overexpressing CAR-T cells sustain lower levels of inhibitory receptors and suppressed tumor recurrence. Collectively, these results define an epigenetic pathway through which H2AFY2 counteracts T cell exhaustion and support the therapeutic potential of H2AFY2-engineered CAR-T cells across tumor types.
PMID:
42578983
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.
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