{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE331nnn/GSE331334/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Genomics"],"species":["Mus musculus"],"gds_type":["Genome binding/occupancy profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE331334"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Y chromosome gene KDM5D coordinates epigenetic and metabolic control of sex differences in CD8⁺ T cell immunity [CUT&Run]","description":"Sex differences in anti-tumor immunity remain incompletely understood yet have important implications for tumor biology and immunotherapy. Here, we combine murine colorectal cancer (CRC) models, primary CD8+ T-cell perturbation studies, and single-cell transcriptomic analyses of human CRC to define a male-biased regulatory axis that limits CD8+ T-cell effector function. Male CD8+ T cells displayed reduced cytokine production, proliferation, cytotoxicity, TCR abundance, and TCR signaling relative to female CD8+ T-cells. Mechanistically, depletion of histone demethylase KDM5D, encoded by the Y chromosome, enhanced TCR expression and clustering, increased proximal TCR signaling, reduced cholesterol biosynthetic programs, and lowered expression of exhaustion-associated genes. In human CRC single-cell datasets, male tumor-infiltrating CD8+ T-cells showed enrichment for exhaustion and cholesterol-associated programs, supporting the translational relevance of this axis. Consistent with the known role of cholesterol in TCR clustering and activation, lovastatin reduced exhaustion-associated marker expression in male CD8+ T-cells and delayed CRC tumor growth in vivo – findings which align with the male-specific CRC risk reduction role of statins. Together, these findings identify KDM5D as a sex-chromosome-linked regulator of male CD8+ T-cell dysfunction and validate cholesterol metabolism as an actionable target for sex-specific immunotherapeutic modulation in cancer.","dates":{"publication":"2026/07/23"},"accession":"GSE331334","cross_references":{"GSM":["GSM9744093","GSM9744097","GSM9744096","GSM9744095","GSM9744094","GSM9744100","GSM9744099","GSM9744098"],"GPL":["19057"],"GSE":["331334"],"taxon":["Mus musculus"]}}