{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T05:47:53Z","timestamp":1782712073678,"version":"3.54.5"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Head and neck squamous cell carcinoma (HNSC) present a significant treatment challenge due to variability in radiotherapy response, where glycolysis may play a pivotal role in modulating sensitivity. This study aimed to develop a glycolysis-associated biomarker for radiotherapy sensitivity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed gene expression and clinical data from 491 HNSC patients and single-cell RNA sequencing to assess glycolysis activity in HNSC. A glycolysis-associated radiosensitivity index (RI) was developed using Cox regression analysis of glycolysis-related genes. Immune microenvironment profiles, functional pathways, and therapeutic responses were analyzed via using ssGSEA, CIBERSORT, TIDE, and pRRophetic.\n                      <jats:italic>In vitro<\/jats:italic>\n                      experiments validated glycolytic activity and radiosensitivity in HNSC cell lines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The study identified that low glycolytic activity significantly correlates with improved overall survival in HNSC patients following radiotherapy, while high glycolytic activity is associated with radio-resistance. Using a RI based on glycolysis-related gene expression, we successfully stratified patients into RS and RR groups. RS tumors exhibited significantly higher immune cell infiltration and lower TIDE scores, indicating a better response to immunotherapy. In contrast, RR tumors showed increased sensitivity to chemotherapy agents, including platinum and EGFR\/HER2 inhibitors. Single-cell RNA sequencing revealed that high-glycolysis tumors had diminished immune cell infiltration, particularly lacking CD8+ T cells, supporting the notion of immune evasion.\n                      <jats:italic>In vitro<\/jats:italic>\n                      validation further demonstrated that radioresistant CAL-27IR cells displayed elevated glycolytic activity and upregulation of key genes associated with the RI, showing the link between glycolysis and radiation resistance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study emphasizes the importance of glycolytic activity in influencing radiotherapy sensitivity and highlights the potential of the RI as a predictive biomarker, paving the way for improved personalized treatment strategies in HNSC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1736778","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T05:39:42Z","timestamp":1782711582000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Evaluating glycolysis-associated biomarkers for radiotherapy sensitivity in head and neck squamous cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Bilan","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Oncology, The Second Affiliated Hospital of Fujian Medical University","place":["Quanzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hainan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University","place":["Xiamen, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyuan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Second Affiliated Hospital of Fujian Medical University","place":["Quanzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinzhi","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Second Affiliated Hospital of Fujian Medical University","place":["Quanzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.35278","article-title":"The GLOBOCAN 2022 cancer estimates: Data sources, methods, and a snapshot of the cancer burden worldwide","volume":"156","author":"Filho","year":"2025","journal-title":"Int J Cancer"},{"key":"B2","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1007\/s11912-019-0856-5","article-title":"Treatment strategy for distant synchronous metastatic head and neck squamous cell carcinoma","volume":"21","author":"Tang","year":"2019","journal-title":"Curr Oncol Rep"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-020-1250-3","article-title":"Radiation resistance in head and neck squamous cell carcinoma: Dire need for an appropriate sensitizer","volume":"39","author":"Hutchinson","year":"2020","journal-title":"Oncogene"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/ijms25063142","article-title":"Targeting the Warburg effect in cancer: Where do we stand","volume":"25","author":"Barba","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2022.09.007","article-title":"Tumor glycolysis, an essential sweet tooth of tumor cells","volume":"86","author":"Paul","year":"2022","journal-title":"Semin Cancer Biol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2025.1540841","article-title":"The gene signature linked to lactate metabolism predicts the prognosis and correlates with the immune status of head and neck squamous cell carcinoma","volume":"16","author":"Xiao","year":"2025","journal-title":"Front Genet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcpro.2023.100551","article-title":"Sulconazole induces PANoptosis by triggering oxidative stress and inhibiting glycolysis to increase radiosensitivity in esophageal cancer","volume":"22","author":"Liu","year":"2023","journal-title":"Mol Cell Proteomics MCP"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-020-04706-0","article-title":"Spatial and quantitative mapping of glycolysis and hypoxia in glioblastoma as a predictor of radiotherapy response and sites of relapse","volume":"47","author":"Leimgruber","year":"2020","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adk3663","article-title":"HSP90 inhibition suppresses tumor glycolytic flux to potentiate the therapeutic efficacy of radiotherapy for head and neck cancer","volume":"10","author":"Chen","year":"2024","journal-title":"Sci Adv"},{"key":"B10","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1186\/s13045-020-01005-x","article-title":"RNA sequencing: New technologies and applications in cancer research","volume":"13","author":"Hong","year":"2020","journal-title":"J Hematol Oncol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2021.113844","article-title":"High-throughput proteomics and AI for cancer biomarker discovery","volume":"176","author":"Xiao","year":"2021","journal-title":"Adv Drug Delivery Rev"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.clon.2015.06.002","article-title":"Biomarkers of tumour radiosensitivity and predicting benefit from radiotherapy","volume":"27","author":"Forker","year":"2015","journal-title":"Clin Oncol (Royal Coll Radiologists (Great Britain))"},{"key":"B13","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/j.ijrobp.2009.05.056","article-title":"Systems biology modeling of the radiation sensitivity network: A biomarker discovery platform","volume":"75","author":"Eschrich","year":"2009","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-13-348","article-title":"Identification of a radiosensitivity signature using integrative metaanalysis of published microarray data for NCI-60 cancer cells","volume":"13","author":"Kim","year":"2012","journal-title":"BMC Genomics"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btab561","article-title":"UCSCXenaShiny: An R\/CRAN package for interactive analysis of UCSC Xena data","volume":"38","author":"Wang","year":"2022","journal-title":"Bioinf (Oxford England)"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-7","article-title":"GSVA: Gene set variation analysis for microarray and RNA-seq data","volume":"14","author":"H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinf"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1020","article-title":"TISCH: A comprehensive web resource enabling interactive single-cell transcriptome visualization of tumor microenvironment","volume":"49","author":"Sun","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1016\/j.cell.2017.10.044","article-title":"Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer","volume":"171","author":"Puram","year":"2017","journal-title":"Cell"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4096","article-title":"Integrating single-cell transcriptomic data across different conditions, technologies, and species","volume":"36","author":"Butler","year":"2018","journal-title":"Nat Biotechnol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac947","article-title":"CellMarker 2.0: An updated database of manually curated cell markers in human\/mouse and web tools based on scRNA-seq data","volume":"51","author":"Hu","year":"2023","journal-title":"Nucleic Acids Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4463","article-title":"SCENIC: Single-cell regulatory network inference and clustering","volume":"14","author":"Aibar","year":"2017","journal-title":"Nat Methods"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.10.003","article-title":"Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer","volume":"39","author":"Bindea","year":"2013","journal-title":"Immunity"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2612","DOI":"10.1038\/ncomms3612","article-title":"Inferring tumour purity and stromal and immune cell admixture from expression data","volume":"4","author":"Yoshihara","year":"2013","journal-title":"Nat Commun"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7493-1_12","article-title":"Profiling tumor infiltrating immune cells with CIBERSORT","volume":"1711","author":"Chen","year":"2018","journal-title":"Methods Mol Biol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0136-1","article-title":"Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response","volume":"24","author":"Jiang","year":"2018","journal-title":"Nat Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0107468","article-title":"pRRophetic: An R package for prediction of clinical chemotherapeutic response from tumor gene expression levels","volume":"9","author":"Geeleher","year":"2014","journal-title":"PloS One"},{"key":"B28","doi-asserted-by":"publisher","first-page":"108","DOI":"10.21037\/atm.2019.12.114","article-title":"Building radiation-resistant model in triple-negative breast cancer to screen radioresistance-related molecular markers","volume":"8","author":"Zhou","year":"2020","journal-title":"Ann Transl Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2022.04.003","article-title":"Radiation therapy-induced remodeling of the tumor immune microenvironment","volume":"86","author":"Charpentier","year":"2022","journal-title":"Semin Cancer Biol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1038\/s41392-023-01462-z","article-title":"Radiation-induced tumor immune microenvironments and potential targets for combination therapy","volume":"8","author":"Guo","year":"2023","journal-title":"Signal Transduction Targeted Ther"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32177","article-title":"Integration of glucose and cardiolipin anabolism confers radiation resistance of HCC","volume":"75","author":"Fang","year":"2022","journal-title":"Hepatol (Baltimore Md)"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.prp.2025.156102","article-title":"METTL1 mediates m7G modification of PFKFB3 mRNA to promote radioresistance in esophageal cancer by affecting glycolytic metabolism","volume":"272","author":"Xiao","year":"2025","journal-title":"Pathol Res Pract"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2023.03.008","article-title":"Glucose metabolism of TAMs in tumor chemoresistance and metastasis","volume":"33","author":"Liu","year":"2023","journal-title":"Trends Cell Biol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1580","DOI":"10.1016\/j.cmet.2023.07.001","article-title":"Tumor aerobic glycolysis confers immune evasion through modulating sensitivity to T cell-mediated bystander killing via TNF-\u03b1","volume":"35","author":"Wu","year":"2023","journal-title":"Cell Metab"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.03.068","article-title":"Increased glycolysis correlates with elevated immune activity in tumor immune microenvironment","volume":"42","author":"Jiang","year":"2019","journal-title":"EBioMedicine"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1111\/odi.14432","article-title":"Metabolic profiling analysis of head and neck squamous cell carcinoma","volume":"30","author":"Ohashi","year":"2024","journal-title":"Oral Dis"},{"key":"B37","doi-asserted-by":"publisher","first-page":"672","DOI":"10.3390\/biology12050672","article-title":"PI3K\/AKT\/mTOR signaling pathway in HPV-driven head and neck carcinogenesis: Therapeutic implications","volume":"12","author":"Aguayo","year":"2023","journal-title":"Biology"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-0413-z","article-title":"Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors","volume":"17","author":"Galluzzi","year":"2020","journal-title":"Nat Rev Clin Oncol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1080\/13543784.2019.1581172","article-title":"Investigational multitargeted kinase inhibitors in development for head and neck neoplasms","volume":"28","author":"Sola","year":"2019","journal-title":"Expert Opin Invest Drugs"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1736778\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T05:39:43Z","timestamp":1782711583000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1736778\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,29]]},"references-count":39,"alternative-id":["10.3389\/fimmu.2026.1736778"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1736778","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,29]]},"article-number":"1736778"}}