JPOST Repositoryapplication/xmlhttps://storage.jpostdb.org/JPST003575/files/20221003_331_mock_pos_DDA_2.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_324_mock_pos_MS1_1.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_324_mock_pos_DDA_1.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_324_JQ1_pos_MS1_5ul_1.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_324_JQ1_pos_DDA_5ul_2.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_331_JQ1_pos_DDA_2.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_324_JQ1_pos_MS1_5ul_2.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_331_JQ1_pos_MS1_2.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_331_mock_pos_MS1_2.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_324_mock_pos_MS1_3.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_324_mock_pos_DDA_2.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_331_mock_pos_DDA_1.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_331_mock_pos_MS1_1.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_331_JQ1_pos_MS1_1.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_324_JQ1_pos_DDA_5ul_1.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_331_JQ1_pos_DDA_1.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_324_JQ1_pos_MS1_5ul_3.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_324_mock_pos_MS1_2.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_331_JQ1_pos_MS1_3.rawhttps://storage.jpostdb.org/JPST003575/files/20221003_331_mock_pos_MS1_3.rawprimaryOK200ProteomicsMiao-Hsia LinHomo Sapiens (human)https://repository.jpostdb.org/entry/JPST003575Department of Microbiology, College of Medicine, National Taiwan UniversityjPOSTfalseEpigenetic modulation of polyamine biosynthetic pathways rectifies T cell dysfunction to enhance anti-tumor immunity in lung cancerT 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 (ODC1), 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.Mon Apr 06 00:00:00 BST 2026PXD0601009606