{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T10:23:31Z","timestamp":1787653411402,"version":"build-2736575974"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Immune checkpoint blockade (ICB) benefits only a minority of patients with triple-negative breast cancer (TNBC), partly because tryptophan catabolism through indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) generates kynurenine, activates aryl hydrocarbon receptor (AhR) signaling, and suppresses CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell function. We investigated whether tanshinone IIA (Tan-IIA) modulates this pathway.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We integrated network pharmacology with TCGA Breast Invasive Carcinoma transcriptomic analyses and evaluated Tan-IIA in 4T1 and MDA-MB-231 cells, tumor-conditioned-medium CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell assays, kynurenine add-back and IDO1-overexpression rescue experiments, and syngeneic 4T1 and EMT6 tumor models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      IDO1 and TDO2 were identified as upregulated Tan-IIA-associated candidates linked to an inflamed-yet-dysfunctional immune phenotype. Tan-IIA dose-dependently suppressed basal and IFN-\u03b3-induced IDO1 and TDO2 expression, reduced the Kyn\/Trp ratio and IDO activity, downregulated AhR target genes in CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, and restored CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell proliferation and effector-marker expression. Exogenous kynurenine and Ido1 overexpression substantially reversed these effects. In vivo, Tan-IIA reduced tumor growth, lowered tumor IDO1 and TDO2 expression, enhanced T-cell infiltration, and showed CD8-dependent antitumor activity. In checkpoint-resistant 4T1 tumors, Tan-IIA combined with anti-PD-1 produced the strongest tumor control and longest survival.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Tan-IIA relieves IDO1\/TDO2\u2013kynurenine\u2013AhR metabolic immunosuppression and sensitizes TNBC to checkpoint blockade, supporting its further evaluation as a microenvironment-remodeling partner for ICB-resistant TNBC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1903253","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T09:59:46Z","timestamp":1787651986000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Tanshinone IIA restores CD8+ T-cell immunity in TNBC by suppressing the IDO1\u2013kynurenine axis"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhu","family":"Qiu","sequence":"first","affiliation":[{"name":"Department of Breast and Thyroid Surgery, Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Meng","sequence":"additional","affiliation":[{"name":"Chongqing Xianxin Medical Technology Co., Ltd.","place":["Chongqing, China"]},{"name":"School of Biomedical Engineering, Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maocai","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, Chongqing University Cancer Hospital","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1038\/nature13323","article-title":"Aryl hydrocarbon receptor control of a disease tolerance defence pathway","volume":"511","author":"Bessede","year":"2014","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1158\/0008-5472.CAN-18-0668","article-title":"IDO1 and kynurenine pathway metabolites activate PI3K-Akt signaling in the neoplastic colon epithelium","volume":"79","author":"Bishnupuri","year":"2019","journal-title":"Cancer Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"4011","DOI":"10.1038\/s41467-020-17750-z","article-title":"Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-kynurenine","volume":"11","author":"Campesato","year":"2020","journal-title":"Nat. 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