{"id":72765,"date":"2026-08-11T19:10:25","date_gmt":"2026-08-11T17:10:25","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2026\/08\/11\/h2afy2-suppresses-exhaustion-and-enhances-antitumor-activity-of-car-t-cells-through-transcriptional-and-epigenetic-modifications\/"},"modified":"2026-08-11T19:10:25","modified_gmt":"2026-08-11T17:10:25","slug":"h2afy2-suppresses-exhaustion-and-enhances-antitumor-activity-of-car-t-cells-through-transcriptional-and-epigenetic-modifications","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2026\/08\/11\/h2afy2-suppresses-exhaustion-and-enhances-antitumor-activity-of-car-t-cells-through-transcriptional-and-epigenetic-modifications\/","title":{"rendered":"H2AFY2 suppresses exhaustion and enhances antitumor activity of CAR-T cells through transcriptional and epigenetic modifications"},"content":{"rendered":"<div>\n<p><b>Cancer Immunol Res<\/b>. 2026 Aug 11. doi: 10.1158\/2326-6066.CIR-25-1334. Online ahead of print.<\/p>\n<p><b>ABSTRACT<\/b><\/p>\n<p>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.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/42578983\/?utm_source=SimplePie&amp;utm_medium=rss&amp;utm_content=101614637&amp;ff=20260811131025&amp;v=2.20.1\">42578983<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.1158\/2326-6066.CIR-25-1334\">10.1158\/2326-6066.CIR-25-1334<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>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 &#8230; <a title=\"H2AFY2 suppresses exhaustion and enhances antitumor activity of CAR-T cells through transcriptional and epigenetic modifications\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2026\/08\/11\/h2afy2-suppresses-exhaustion-and-enhances-antitumor-activity-of-car-t-cells-through-transcriptional-and-epigenetic-modifications\/\" aria-label=\"Read more about H2AFY2 suppresses exhaustion and enhances antitumor activity of CAR-T cells through transcriptional and epigenetic modifications\">Read more<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[55,42],"tags":[],"class_list":["post-72765","post","type-post","status-publish","format-standard","hentry","category-cancer-immunology-reserch","category-publicaciones"],"_links":{"self":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/72765","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/comments?post=72765"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/72765\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=72765"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=72765"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=72765"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}