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However, whether adaptive immune cells also play an important role in pre-metastatic niche formation remains to be explored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell accumulation in tumor-free lung tissues from mice bearing subcutaneous mouse tumors was detected by immunofluorescence\/confocal microscopy. Tumor-conditioned media (TCM) from MB49-\n                      <jats:italic>S1pr1<\/jats:italic>\n                      <jats:sup>high<\/jats:sup>\n                      mouse bladder tumor cells or ID8 ovarian tumor cells were administered to tumor-free mice to induce pre-metastatic niche formation. We used mice lacking functional Signal Transducer and Activator of Transcription 3 (STAT3) in T cells and\n                      <jats:italic>\n                        Il17a\n                        <jats:sup>\u2012\/\u2012<\/jats:sup>\n                      <\/jats:italic>\n                      mice to investigate the roles of STAT3 and interleukin (IL)-17. In vivo time-course experiments were performed to assess whether CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell clusters contribute to CD11b\n                      <jats:sup>+<\/jats:sup>\n                      pre-metastatic clusters. CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell migration and chemokine receptor expression assays were employed to identify tumor factors driving CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell recruitment. A co-culture system with human MRC-5 lung fibroblasts, healthy donor-derived CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells, myeloid cells, and TCM derived from human cancer cells was used to evaluate CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell-driven fibroblast activation and IL-17A dependency for myeloid cell migration. Microscopic analyses were performed to confirm CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell clusters in tumor-free lymph node tissues from patients with prostate cancer and postmortem lung and liver specimens from patients with ovarian cancer.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We demonstrate that CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells accumulate in tumor-free lungs and promote tumor metastasis in mouse models. CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cell pre-metastatic niche formation requires STAT3, which regulates Th17 CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells. TCM drives IL-6-dependent CCR4\/CCR6 upregulation on naive CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells. CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell clusters contribute to myeloid cell accumulation, and ablating STAT3 in T cells abrogates both T cell and myeloid cluster formation. IL-17 inhibition reduces myeloid lung infiltration. In human co-cultures, CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells amplify TCM-induced fibroblast pre-metastatic niche-like activation and myeloid recruitment in an IL-17A-dependent manner. CD4\n                      <jats:sup>+<\/jats:sup>\n                      and IL-17\n                      <jats:sup>+<\/jats:sup>\n                      or p-STAT3\n                      <jats:sup>+<\/jats:sup>\n                      clusters were also detected in non-metastatic tissues from patients with several cancers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells form pre-metastatic niches through the STAT3-IL-17 axis, contributing to myeloid cell cluster formation, in part through amplifying fibroblast pre-metastatic niche-like activation. STAT3 and IL-17 in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells therefore are important for pre-metastatic niche formation and metastasis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013183","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T12:45:22Z","timestamp":1786711522000},"page":"e013183","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["T cells are critical for pre-metastatic niche formation through the STAT3\/IL-17 axis"],"prefix":"10.1136","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9701-5211","authenticated-orcid":false,"given":"Maciej","family":"Kujawski","sequence":"first","affiliation":[{"name":"Immunology and Theranostics, City of Hope Beckman Research Institute, Duarte, California, 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