{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:11:54Z","timestamp":1784679114515,"version":"3.55.0"},"reference-count":104,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T00:00:00Z","timestamp":1762819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Auranofin, an FDA-approved antirheumatic drug and thioredoxin reductase 1 (TXNRD1) inhibitor, has demonstrated anti-tumoral properties, but its immunological effects are not well characterized. Here, we report that auranofin unexpectedly promotes regulatory T cell (Treg) expansion. In a B16F10 melanoma model, auranofin treatment increased lung tumor coverage, IL-10 serum levels, and FOXP3+CD44+CD4+ T cell frequencies. It also altered the proportion of antigen-presenting cells (APCs), increasing B cells and reducing dendritic cells. To test whether Treg expansion occurs independently of tumor antigens, we stimulated T cells ex vivo in lymph node cultures from na\u00efve mice using anti-CD3\/CD28, with or without auranofin. Auranofin increased Treg frequency in these cultures, as well as in treated human PBMCs. Similar effects were observed with the TXNRD1 inhibitor TRi-1, suggesting a ROS-dependent mechanism. Using mice with conditional expression of neutrophil cytosolic factor 1 (NCF1), we found that both TXNRD1 inhibition and APC-specific NCF1-NOX2-ROS expression enhanced tumor burden and Treg expansion. Alternatively, sorted T cells from mice harboring conditional TXNRD1 knockouts showed reduced FOXP3 and GITR expression in the na\u00efve state and reduced tumor burden when challenged with B16F10. These data suggest TXNRD1 inhibitors likely drive Treg expansion by elevating ROS levels in APCs during T cell priming and less by intrinsic Treg TXNRD1 blockade. Our findings reveal a paradoxical immunosuppressive effect of TXNRD1 inhibitors that may contribute to their limited efficacy in immunocompetent cancer models. This work provides mechanistic insight and underscores the need to consider Treg-mediated immune suppression when designing TXNRD1-targeted therapies.<\/jats:p>","DOI":"10.3390\/antiox14111351","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T10:56:27Z","timestamp":1762858587000},"page":"1351","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Anti-Tumoral Treatment with Thioredoxin Reductase 1 Inhibitor Auranofin Fosters Regulatory T Cell and B16F10 Expansion in Mice"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8184-0954","authenticated-orcid":false,"given":"Michael Y.","family":"Bonner","sequence":"first","affiliation":[{"name":"Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5892-3682","authenticated-orcid":false,"given":"Tamas","family":"Vancsik","sequence":"additional","affiliation":[{"name":"Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7783-9750","authenticated-orcid":false,"given":"Ana","family":"Oliveira-Coelho","sequence":"additional","affiliation":[{"name":"Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2734-1791","authenticated-orcid":false,"given":"Pierre","family":"Sabatier","sequence":"additional","affiliation":[{"name":"Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9100-8283","authenticated-orcid":false,"given":"Christian M.","family":"Beusch","sequence":"additional","affiliation":[{"name":"Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kejsi","family":"Zeqiraj","sequence":"additional","affiliation":[{"name":"Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolin","family":"Svensson","sequence":"additional","affiliation":[{"name":"Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9839-2089","authenticated-orcid":false,"given":"Roman A.","family":"Zubarev","sequence":"additional","affiliation":[{"name":"Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4807-6114","authenticated-orcid":false,"given":"Elias S. J.","family":"Arn\u00e9r","sequence":"additional","affiliation":[{"name":"Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65 Solna, Sweden"},{"name":"Department of Selenoprotein Research and the National Tumor Biology Laboratory, National Institute of Oncology, 1122 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4969-2576","authenticated-orcid":false,"given":"Rikard","family":"Holmdahl","sequence":"additional","affiliation":[{"name":"Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1002\/med.21872","article-title":"Upgrade of an old drug: Auranofin in innovative cancer therapies to overcome drug resistance and to increase drug effectiveness","volume":"42","author":"Gamberi","year":"2022","journal-title":"Med. 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