Cancer Immunol Res. 2026 Aug 11. doi: 10.1158/2326-6066.CIR-25-1334. Online ahead of print.
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 | DOI:10.1158/2326-6066.CIR-25-1334