{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:19:25Z","timestamp":1785435565308,"version":"3.56.0"},"reference-count":48,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["CSDG-25-1513999-01-IBCD"],"award-info":[{"award-number":["CSDG-25-1513999-01-IBCD"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"award":["CSDG-25-1513999-01-IBCD"],"award-info":[{"award-number":["CSDG-25-1513999-01-IBCD"]}],"id":[{"id":"https:\/\/ror.org\/02e463172","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: T cells within solid tumors often switch from a recirculating to a tissue-resident state, which may blunt antitumor activity, but the signal driving this switch in vivo remains unclear. We asked whether alterations in sphingosine-1-phosphate (S1P) signaling in tumor or the surrounding stromal cells are associated with T cell residency in glioblastoma (GBM). Methods: We analyzed five single-cell RNA-sequencing cohorts: three human glioma datasets, an in-house mouse CT2A glioblastoma cohort, and a human melanoma tumor-infiltrating lymphocyte cohort. T cell egress and tissue-residency programs, together with stromal S1P production and degradation, were scored per cell using curated gene modules. Cell-state contrasts were quantified as Cohen\u2019s d, and sample-level coupling as Spearman \u03c1. Results: In human GBM, T cell residency programs were elevated in CD4+ helper and regulatory T cells in tumors compared with low-grade glioma controls. In mouse CT2A-derived GBM tumors, stromal S1P production correlated negatively with T cell residency across four independent stromal cell types. In human GBM microglia, S1P production was reduced compared with control microglia. The same CD8+ residency phenotype was replicated in CD3-sorted GBM tumor-infiltrating lymphocytes (TILs) and in melanoma TILs. Conclusions: A loss of stromal S1P production accompanies T cell tissue residency in GBM. Thus, stromal S1P metabolism is a candidate axis for modulating T cell recirculation and TIL biology in GBM. These findings are transcriptomic associations from single-cell RNA sequencing that do not directly measure S1P metabolite levels or signaling activity and will require functional and lipidomic validation.<\/jats:p>","DOI":"10.3390\/cancers18132168","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T12:01:37Z","timestamp":1783339297000},"page":"2168","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tumor and Stromal Sphingolipid Imbalance Are Associated with T Cell Tissue Residency in Glioblastoma"],"prefix":"10.3390","volume":"18","author":[{"given":"Chase M.","family":"Walton","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA"},{"name":"Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elif","family":"Percin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA"},{"name":"Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4552-4436","authenticated-orcid":false,"given":"Han Gyul","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA"},{"name":"Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odai","family":"Darawsha","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA"},{"name":"Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben A.","family":"Strickland","sequence":"additional","affiliation":[{"name":"Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA"},{"name":"Department of Neurosurgery, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1019-5660","authenticated-orcid":false,"given":"Besim","family":"Ogretmen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA"},{"name":"Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJMoa043330","article-title":"Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N. 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