GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE287nnn/GSE287799/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE287799GEOGSEfalseEpigenetic modulation of polyamine biosynthetic pathways rectifies T cell dysfunction to enhance anti-tumor immunity in lung cancer [RNA-seq]T cell exhaustion (TEX) represents a critical target for immunotherapy in cancer. Nevertheless, T cells exhibit diminished responsiveness to immune checkpoint inhibitors once they transition to a terminally-exhausted state. Here, we employed an epigenetic drug screen and identified BET inhibitors (BETis) as enhancers of effector functions in primary exhausted T cells from malignant pleural effusions in lung cancer patients. Transcriptomics, metabolomics, and ATAC-seq analyses revealed that BETis reinvigorate TEX by activating the polyamine biosynthesis pathway, expanding intracellular polyamine pools, and altering chromatin accessibility. Genetic and pharmacological inhibition of ornithine decarboxylase (ODC), a key enzyme in this pathway, abolished BETi-mediated immunopotentiation. Single-cell RNA-seq demonstrated BETis reduced terminal TEX while promoting progenitor TEX through activation of the MYC-ODC axis. BETi treatment or adoptive transfer of BETi-treated T cells suppressed malignant pleural effusion formation in a syngeneic lung cancer model. These findings highlight an epigenetic-metabolic approach to enhance TEX plasticity and offers insights for novel cancer immunotherapies.2026/04/05GSE287799GSM8751553GSM8751556GSM8751557GSM8751554GSM8751555GSM875155824676287799Homo sapiens