{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T10:07:13Z","timestamp":1771927633167,"version":"3.50.1"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Cytotoxic T lymphocytes (CTLs, mainly CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells) are the primary killer cells in the tumor microenvironment (TME). This study investigates the expression of LAG-3 in the TME of cervical cancer and its regulatory role in CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Cervical tissue pathological sections and fresh cervical tissues were collected from patients with cervical cancer, patients with high-grade squamous intraepithelial lesion (HSIL), and patients who underwent hysterectomy for non-cervical diseases (without a history of other tumors). Immunohistochemistry, Western blotting, quantitative real-time PCR, and fluorescence imaging techniques were used to analyze the expression of LAG-3 in the cervical cancer TME and its correlation with clinical tumor stage, differentiation grade, lymph node metastasis status, and lymphovascular space invasion. A cell co-culture system and a cervical cancer mouse model were established to evaluate the effects of lag-3 on tumor growth and changes in CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      LAG-3 is highly expressed in the tumor microenvironment (TME) of cervical cancer, with its expression level increasing as the tumor stage progresses: the lower the degree of differentiation, the higher the LAG-3 expression; LAG-3 expression is also elevated in cases with lymph node metastasis and lymphovascular space invasion.\n                      <jats:italic>In vivo<\/jats:italic>\n                      mouse models confirmed that lag-3 inhibits CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells from expressing Ki67, T-bet, TNF-\u03b1, IFN-\u03b3, and IL-2. Furthermore, we found that lag-3 not only suppresses the differentiation of naive CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells into central memory T cells (TCM) but also inhibits the differentiation of TCM into effector memory T cells (TEM), a subset with stronger anti-tumor effector functions. A similar phenomenon was observed in cell co-culture experiments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      We confirmed that LAG-3 is highly expressed in cervical cancer tissues and is closely correlated with clinical stage, differentiation grade, lymph node metastasis, and lymphovascular space invasion. LAG-3 may inhibit the function of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells in the cervical cancer TME, thereby promoting the progression of cervical cancer.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1750726","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T06:44:09Z","timestamp":1769582649000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["LAG-3\u2013associated CD8+ T-cell dysfunction in the cervical cancer tumor microenvironment"],"prefix":"10.3389","volume":"17","author":[{"given":"Guang","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Gynecology, The First Afffliated Hospital of Xinjiang Medical University","place":["Urumqi, Xinjiang, China"]},{"name":"State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central 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