{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T22:21:42Z","timestamp":1787610102571,"version":"build-2736575974"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"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. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitor (ICI) therapy for oral squamous cell carcinoma (OSCC) yields objective responses in fewer than 20% of patients, underscoring the urgent need for novel predictive biomarkers beyond PD-L1 expression and tumor mutational burden (TMB). Ferroptosis, an iron-dependent oxidative cell death program, has emerged as a dual-function regulator of tumor immunity. Whether ferroptotic dysregulation of the PDL stromal compartment and MT1\/MT2 suppression constitute novel mechanistic determinants of ICI resistance in OSCC remains poorly understood and warrants mechanistic investigation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed a single-cell RNA sequencing (scRNA-seq) analysis of a publicly available multi-regional OSCC dataset (GEO: GSE198315; adjacent non-tumor [NT], tumor core [TC], and metastatic lymph node [mLN]; 22,371 quality-controlled cells), encompassing dimensionality reduction, pseudotemporal trajectory reconstruction, immune checkpoint gene profiling (PD-1\/PD-L1\/CTLA-4\/TIM-3\/LAG-3), ferroptosis\u2013immune crosstalk inference, and intercellular communication modeling. To experimentally validate key computational findings, we performed\n                      <jats:italic>in vitro<\/jats:italic>\n                      RT-qPCR experiments in primary human PDL fibroblasts exposed to oxidative conditioned medium (OCM), quantifying the expression of GPX4, ACSL4, MTNR1A (MT1), MTNR1B (MT2), and CD274 (PD-L1) at 24\u00a0h and 48\u00a0h.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      scRNA-seq revealed that OCM-exposed PDL cells exhibited a 3.2-fold elevation in the ferroptotic index, co-occurring with profound MT1\/MT2 suppression and circadian axis disruption. Ferroptosis-susceptible PDL subpopulations showed coordinated upregulation of immunosuppressive ligands (PD-L1, CD47, and Galectin-9), reduced CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell infiltration scores, and enhanced myeloid-derived suppressor cell (MDSC) and tumor-associated macrophage (TAM) recruitment signals, suggesting a mechanistic association between PDL stromal ferroptosis and immune checkpoint-mediated immune evasion.\n                      <jats:italic>In vitro<\/jats:italic>\n                      RT-qPCR validation in primary human PDL fibroblasts (ATCC PCS-201-018) exposed to OCM confirmed significant downregulation of GPX4, SLC7A11 (xCT), MTNR1A (MT1), and MTNR1B (MT2), concurrent with the upregulation of ACSL4 and CD274 (PD-L1) at both 24\u00a0h and 48\u00a0h (all\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.05), directly corroborating the scRNA-seq-predicted ferroptosis\u2013melatonin receptor\u2013immune checkpoint co-regulatory axis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      We establish a mechanistically grounded framework suggesting that PDL stromal ferroptosis and MT1 suppression constitute novel components of the OSCC tumor immune evasion landscape.\n                      <jats:italic>In vitro<\/jats:italic>\n                      RT-qPCR validation supports the ferroptosis\u2013melatonin receptor\u2013immune checkpoint co-regulatory axis as a candidate therapeutic target to overcome immunotherapy resistance in oral cancer, pending prospective clinical validation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1911302","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T22:10:52Z","timestamp":1787609452000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Ferroptosis-driven stromal immune evasion and melatonin receptor suppression as novel predictive biomarkers of immunotherapy response in oral squamous cell carcinoma: a single-cell transcriptomic study"],"prefix":"10.3389","volume":"17","author":[{"given":"Lu","family":"Han","sequence":"first","affiliation":[{"name":"Department of Orthodontics, School and Hospital of Stomatology, Wenzhou Medical University","place":["Wenzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conghui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Hainan General Hospital, Affiliated Hainan Hospital of Hainan Medical University","place":["Haikou, Hainan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.1016\/s0140-6736(19)32591-7","article-title":"Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study","volume":"394","author":"Burtness","year":"2019","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"5649","DOI":"10.3390\/ijms22115649","article-title":"Melatonin downregulates PD-L1 expression and modulates tumor immunity in KRAS-mutant non-small cell lung cancer","volume":"22","author":"Chao","year":"2021","journal-title":"Int. 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