{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T15:56:02Z","timestamp":1774454162208,"version":"3.50.1"},"reference-count":40,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology, Taiwan\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/02kv4zf79","award":["108-2320-B-303-004-MY3"],"award-info":[{"award-number":["108-2320-B-303-004-MY3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>The programmed death-ligand 1 (PD-L1) plays a critical role for promoting cancer immune evasion. However, the resistance to PD-L1-targeted immunotherapy greatly limits its application. \u03b1-lipoic acid (ALA) is an endogenous antioxidant, while whether ALA affects PD-L1 expression remains unknown. In IFN-\u03b3-stimulated castration-resistant prostate cancer (CRPC)-mimicking PC3 and DU145 cells, the expression of PD-L1 and its regulatory genes was determined by Western blotting, RT-PCR, and immunofluorescence. The T-cell-mediated tumor-killing activity was evaluated in a co-culture system of cancer cells and Jurkat T cells. ALA significantly inhibits IFN-\u03b3-induced PD-L1 protein and mRNA expression without affecting its degradation. The upstream genes accounting for PD-L1 induction, including JAK1\/STAT1\/IRF-1 cascade, c-Myc, HIF-1\u03b1, and GSK3\u03b2 activity, were markedly suppressed by ALA. The decreased expression of PD-L1 and these regulators by ALA is also modulated by attenuation of mTOR\/p70S6K\/4EBP1-dependent protein translation and ROS production. In the co-culture system, ALA markedly increased T-cell-mediated tumor-killing activity compared to that of ALA treatment alone, suggesting that ALA may augment the antitumor immunity. Collectively, we demonstrated that ALA-mediated inhibition of PD-L1 expression is regulated by multiple mechanisms, which indicates that ALA may be a potential agent to enhance cancer immunotherapy, particularly in CRPC.<\/jats:p>","DOI":"10.3390\/antiox15040413","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T15:05:33Z","timestamp":1774451133000},"page":"413","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Alpha-Lipoic Acid Inhibits IFN-\u03b3-Induced PD-L1 Expression in Prostate Cancer Cells and Enhances T-Cell-Mediated Anti-Tumor Cytotoxicity"],"prefix":"10.3390","volume":"15","author":[{"given":"Yi-Jan","family":"Hsia","sequence":"first","affiliation":[{"name":"Dental Department, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan"},{"name":"Devision of Oral and Maxillofacial Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1378-9978","authenticated-orcid":false,"given":"Zhang-Min","family":"Lin","sequence":"additional","affiliation":[{"name":"Cathay Medical Research Institute, Cathay General Hospital, New Taipei City 22174, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0515-1855","authenticated-orcid":false,"given":"Tien-Sheng","family":"Tseng","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology, National Chung Hsing University, Taichung 402805, Taiwan"},{"name":"Doctoral Program in Microbial Genomics, National Chung Hsing University and Academia Sinica, Taipei 115024, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tz-Chong","family":"Chou","sequence":"additional","affiliation":[{"name":"Cathay Medical Research Institute, Cathay General Hospital, New Taipei City 22174, Taiwan"},{"name":"Graduate Institute of Medical Sciences, National Defense Medical University, Taipei 11490, Taiwan"},{"name":"Department of Pharmacology, National Defense Medical University, Taipei 11490, Taiwan"},{"name":"China Medical University Hospital, China Medical University, Taichung 404327, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.18632\/oncotarget.13895","article-title":"PD-1 and its ligands are important immune checkpoints in cancer","volume":"8","author":"Dong","year":"2017","journal-title":"Oncotarget"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1158\/1078-0432.CCR-15-2042","article-title":"The immune checkpoint regulator PD-L1 is highly expressed in aggressive primary prostate cancer","volume":"22","author":"Gevensleben","year":"2016","journal-title":"Clin. 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