{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T05:32:58Z","timestamp":1784957578326,"version":"3.55.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:00:00Z","timestamp":1761523200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018779","name":"Fundaci\u00f3n Fero","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100018779","id-type":"DOI","asserted-by":"publisher"}]}],"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>In Cutaneous T-cell Lymphoma (CTCL), T cells can be activated either by cytokines produced by malignant T cells or through immunological synapses, such as the interaction between OX-40 and OX-40L on dendritic cells. Both are co-expressed in tumor cells in Mycosis fungoides\/S\u00e9zary syndrome and correlate with disease severity markers. Using a model of spontaneous metastasis in chick embryos, the present study aimed to determine the functional role of OX-40 in CTCL and assess its potential as a therapeutic target.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>OX-40 knockout MyLa and SeAx CTCL cells using CRISPR-Cas9 were engrafted onto the chorioallantoic membrane of chick embryos. We assessed tumor growth, dissemination, and TME modulation in the presence or absence of macrophages. Transwell-based transendothelial migration assays and co-culture experiments were performed to further explore the interactions between CTCL cells and macrophages. Angiogenesis and lymphangiogenesis have also been investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>OX-40 expression promoted intravasation, metastasis, and cytokine secretion, and increased M2 macrophages. Additionally, it restores transendothelial migration and dissemination in the presence of M2 macrophages, possibly through ERK activation. Co-culture experiments revealed that OX-40 promoted a Th2 cytokine profile in CTCL, correlating with M2 macrophages in xenografts. Although OX-40 did not affect angiogenesis in this model, it promoted lymphangiogenesis via VEGF-C expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Using the CTCL spontaneous metastasis model in chick embryos, we demonstrated that OX-40 regulates the TME to promote M2 increase, lymphangiogenesis, CAM intravasation, and metastasis. Therefore, the\n                      <jats:italic>in vivo<\/jats:italic>\n                      chick embryo metastasis model may serve as a valuable preclinical tool for identifying novel anti-tumor targets in CTCL. The OX-40 axis was identified as a key driver of CTCL progression, promoting tumor growth and metastasis through ERK activation while validating the chick embryo model as a preclinical tool for therapeutic testing.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1677140","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T06:21:32Z","timestamp":1761546092000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["OX-40 signaling promotes tumorigenesis in CTCL by regulating ERK 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