{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:57:54Z","timestamp":1789480674778,"version":"build-2803163510"},"reference-count":16,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T00:00:00Z","timestamp":1772928000000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100020784","name":"Gannan Medical University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020784","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>To investigate the role and mechanism of SLC12A8 in the progression of Luminal B breast cancer.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Data from TCGA, GTEx, and HPA databases were used to analyze SLC12A8 expression and its prognostic value in breast cancer. qPCR was performed to validate SLC12A8 expression in various breast cancer cell lines. The correlation between SLC12A8 and immune cell infiltration was analyzed using ImmuCellAI and TIMER databases. Gene set enrichment analysis (GSEA) was employed to predict signaling pathways associated with SLC12A8. In\u00a0vitro, siRNA\u2010mediated knockdown of SLC12A8 or treatment with the TLR pathway inhibitor GIT27 was used to assess the effects on the TLR pathway, CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell function (as indicated by PD\u20101, PRF1, and GZMB expression), and cancer cell invasion via Western blot, immunofluorescence, qPCR, and Transwell assays. CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells were isolated from healthy human peripheral blood using magnetic bead separation (Miltenyi Biotec, CD8 MicroBeads) and activated with anti\u2010CD3\/CD28 beads prior to co\u2010culture. Additional functional assays included IFN\u2010\u03b3\/IL\u20102 ELISA and cytotoxicity assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SLC12A8 was significantly upregulated in breast cancer tissues and cell lines, and its high expression correlated with poor patient prognosis. Bioinformatic analysis and experimental validation confirmed that high SLC12A8 expression was strongly associated with reduced infiltration and functional inhibition of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells in the tumor microenvironment, particularly in Luminal B breast cancer. Mechanistically, SLC12A8 activated the TLR signaling pathway (upregulating TLR2, MyD88, IRAK1, TAK1 in CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells), leading to increased PD\u20101 expression on CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, resulting in their functional exhaustion and enhanced invasive ability of Luminal B breast cancer cells. Knockdown of SLC12A8 or TLR pathway inhibition reversed these effects. Overexpression of SLC12A8 in normal breast epithelial cells recapitulated the exhausted T\u2010cell phenotype, and TLR2 agonist treatment mimicked SLC12A8 effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      SLC12A8 promotes immune evasion and metastasis in Luminal B breast cancer by inducing CD8\n                      <jats:sup>+<\/jats:sup>\n                      T\u2010cell exhaustion via activation of the TLR signaling pathway, suggesting its potential as a prognostic biomarker and therapeutic target.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.71712","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T19:25:50Z","timestamp":1772997950000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<scp>SLC12A8<\/scp>\n                    Drives Immune Evasion and Metastasis in Luminal B Breast Cancer by Inducing\n                    <scp>CD8<\/scp>\n                    <sup>+<\/sup>\n                    T\u2010Cell Exhaustion via the\n                    <scp>TLR<\/scp>\n                    Signaling Pathway"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3277-7626","authenticated-orcid":false,"given":"Zhiyong","family":"Liu","sequence":"first","affiliation":[{"name":"Breast Treatment Center, the First Affiliated Hospital of Gannan Medical University  Ganzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Chen","sequence":"additional","affiliation":[{"name":"Breast Treatment Center, the First Affiliated Hospital of Gannan Medical University  Ganzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,8]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/bcr2904"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3862"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111131"},{"issue":"9","key":"e_1_2_13_6_1","first-page":"1613","article-title":"SLC12A8 Promotes Proliferation, Invasiveness, Migration and Epithelial\u2010Mesenchymal Transition of Bladder Cancer Cells by Activating JAK\/STAT Signaling","volume":"43","author":"Zhang X.","year":"2023","journal-title":"Nan Fang Yi Ke Da Xue Xue Bao"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1515\/med-2021-0013"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-023-05416-4"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2024.148211"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.00547"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxab050"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3861"},{"issue":"24","key":"e_1_2_13_13_1","first-page":"7454","article-title":"TLR4 Signaling Promotes Tumor\u2010Induced Immunosuppression by Increasing Hyaluronan Production","volume":"73","author":"Rajput S.","year":"2013","journal-title":"Cancer 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