{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T02:08:13Z","timestamp":1789783693852,"version":"4.0.1"},"reference-count":113,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014069","name":"Champalimaud Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100014069","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/03g001n57","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has achieved clinically and biologically relevant responses in patients with solid cancer. Clinical efficacy has been increasingly linked to a specific T-cell phenotype, particularly CD8+ TILs exhibiting a progenitor stem-cell-like profile (CD39\u2212 CD69\u2212). This review explores the critical role of the sphingosine-1-phosphate (S1P) axis in orchestrating these responses. We detail the biological antagonism between the activation marker CD69 and S1P receptor 1 (S1PR1), where mutual exclusivity dictates thymic selection, if T-cells are retained in tissues or allowed to recirculate and maintain long-term immune surveillance. The S1PR1:S1P axis is further recognized as a critical regulator of mitochondrial fitness, sustaining the high energetic demands of precursor T-cells. We examine the \u201cdouble-edged sword\u201d nature of S1P in the tumor microenvironment (TME), where it can drive pro-tumorigenic processes like angiogenesis and vascular mimicry (VM), be hijacked by cancer cells to create immune-excluded environments, or S1P can increase T-cell fitness. We summarize the current landscape of clinical trials (as of January 2026) that target S1P production or signaling to modulate anti-tumor responses or use S1P as a biologically relevant marker of treatment outcome.<\/jats:p>","DOI":"10.3390\/cells15100909","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T08:06:26Z","timestamp":1779696386000},"page":"909","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["S1P in Tumor Microenvironment and Modulation of Anti-Tumor-Directed T-Cell Responses"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-4053-9646","authenticated-orcid":false,"given":"Patr\u00edcia A.","family":"Ant\u00f3nio","sequence":"first","affiliation":[{"name":"Immunotherapy\/ImmunoSurgery Laboratory, Cell Center at the Champalimaud Foundation, Avenida Bras\u00edlia, 1400-038 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9874-5259","authenticated-orcid":false,"given":"Joana R.","family":"L\u00e9rias","sequence":"additional","affiliation":[{"name":"Immunotherapy\/ImmunoSurgery Laboratory, Cell Center at the Champalimaud Foundation, Avenida Bras\u00edlia, 1400-038 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina M.","family":"Gorgulho","sequence":"additional","affiliation":[{"name":"Immunotherapy\/ImmunoSurgery Laboratory, Cell Center at the Champalimaud Foundation, Avenida Bras\u00edlia, 1400-038 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina","family":"Balan","sequence":"additional","affiliation":[{"name":"Immunotherapy\/ImmunoSurgery Laboratory, Cell Center at the Champalimaud Foundation, Avenida Bras\u00edlia, 1400-038 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vitaly","family":"Balan","sequence":"additional","affiliation":[{"name":"Immunotherapy\/ImmunoSurgery Laboratory, Cell Center at the Champalimaud Foundation, Avenida Bras\u00edlia, 1400-038 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus J.","family":"Maeurer","sequence":"additional","affiliation":[{"name":"Immunotherapy\/ImmunoSurgery Laboratory, Cell Center at the Champalimaud Foundation, Avenida Bras\u00edlia, 1400-038 Lisbon, Portugal"},{"name":"I Med Clinic, Johannes Gutenberg University of Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"ref_1","unstructured":"US Food and Drug Administration (2025, January 30). 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