{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T04:16:20Z","timestamp":1788322580994,"version":"build-2803163510"},"reference-count":50,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Beijing Natural Science Foundation","award":["7262148"],"award-info":[{"award-number":["7262148"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173307"],"award-info":[{"award-number":["82173307"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Neoadjuvant chemoimmunotherapy has emerged as a promising treatment strategy for head and neck squamous cell carcinoma (HNSCC). There is an urgent need to improve patient responses to this approach. In this study, we aim to elucidate the mechanisms underlying poor response to neoadjuvant chemoimmunotherapy and to identify strategies to enhance therapeutic efficacy in HNSCC. We identified a cancer stem-like cell (CSC) population enriched in patients with partial response (PR) to neoadjuvant chemoimmunotherapy, characterized by high CD80 expression. CD80 was likewise highly expressed in ALDHhighCD44+ and BMI1+ populations. Functionally, CD80 knockdown attenuated tumor-sphere-forming capacity and reduced the migration and invasion of tumor cells, whereas CD80 overexpression potentiated these pro-tumorigenic activities. Moreover, CD80 inhibition activated signaling pathways of Th1 immune responses and IL-2 production. CD80 blockade enhanced T cell cytotoxicity. In preclinical HNSCC models, inhibition of CD80 significantly decreased tumor burden, accumulated CD8+ T cells, and increased the production of cytotoxic effector molecules. Our data demonstrated that CD80 modulated tumor-cell stemness and malignant phenotype while restraining antitumor T cell immunity. Targeting CD80 augments antitumor immunity and provides a compelling strategy to enhance treatment responses to neoadjuvant chemoimmunotherapy in HNSCC.<\/jats:p>","DOI":"10.3390\/cells15030266","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T13:04:46Z","timestamp":1769778286000},"page":"266","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["CD80-Mediated T-Cell Suppression by Cancer Stem-like Cells in Head and Neck Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"15","author":[{"given":"Mian","family":"Xiao","sequence":"first","affiliation":[{"name":"Central Laboratory, Peking University School and Hospital of Stomatology, Beijing 100081, China"},{"name":"National Clinical Research Center for Oral Diseases, Beijing 100081, China"},{"name":"National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing 100081, China"},{"name":"Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China"},{"name":"Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruifeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanrui","family":"Feng","sequence":"additional","affiliation":[{"name":"Central Laboratory, Peking University School and Hospital of Stomatology, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefen","family":"Li","sequence":"additional","affiliation":[{"name":"Central Laboratory, Peking University School and Hospital of Stomatology, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6012-2398","authenticated-orcid":false,"given":"Xiyuan","family":"Ge","sequence":"additional","affiliation":[{"name":"Central Laboratory, Peking University School and Hospital of Stomatology, Beijing 100081, China"},{"name":"National Clinical Research Center for Oral Diseases, Beijing 100081, China"},{"name":"National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing 100081, China"},{"name":"Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China"},{"name":"Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,30]]},"reference":[{"key":"ref_1","first-page":"17","article-title":"Cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e188128","DOI":"10.1172\/JCI188128","article-title":"Immunotherapeutic strategies in head and neck cancer: Challenges and opportunities","volume":"135","author":"Liu","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"102938","DOI":"10.1016\/j.ctrv.2025.102938","article-title":"Management approaches for recurrent or metastatic head and neck squamous cell carcinoma after anti-PD-1\/PD-L1 immunotherapy","volume":"136","author":"Tahara","year":"2025","journal-title":"Cancer Treat. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.it.2022.04.010","article-title":"Turning cold tumors hot: From molecular mechanisms to clinical applications","volume":"43","author":"Zhang","year":"2022","journal-title":"Trends Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1002\/cac2.12178","article-title":"Advancing to the era of cancer immunotherapy","volume":"41","author":"Wang","year":"2021","journal-title":"Cancer Commun."},{"key":"ref_6","doi-asserted-by":"crossref","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":"ref_7","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1200\/JCO.22.00332","article-title":"Nivolumab Plus Ipilimumab Versus EXTREME Regimen as First-Line Treatment for Recurrent\/Metastatic Squamous Cell Carcinoma of the Head and Neck: The Final Results of CheckMate 651","volume":"41","author":"Haddad","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Wu, W.J., Liu, Q., An, P.G., Wang, L., Zhang, J.Y., Chen, Y., Zhang, T., and Zhang, J. (2023). Neoadjuvant tislelizumab combined with chemotherapy in locally advanced oral or oropharyngeal squamous cell carcinoma: A real-world retrospective study. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1282629"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/j.ccell.2023.04.014","article-title":"Tislelizumab plus chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal cancer: A multicenter phase 3 trial (RATIONALE-309)","volume":"41","author":"Yang","year":"2023","journal-title":"Cancer Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2568","DOI":"10.1038\/s41591-024-03110-7","article-title":"Finotonlimab with chemotherapy in recurrent or metastatic head and neck cancer: A randomized phase 3 trial","volume":"30","author":"Shi","year":"2024","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1186\/s12943-025-02487-4","article-title":"Neoadjuvant immunotherapy in squamous cell carcinoma of the head and neck: Current evidence and future perspectives","volume":"24","author":"Zhang","year":"2025","journal-title":"Mol. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3983","DOI":"10.1073\/pnas.0530291100","article-title":"Prospective identification of tumorigenic breast cancer cells","volume":"100","author":"Wicha","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/nature13305","article-title":"SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma","volume":"511","author":"Boumahdi","year":"2014","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.stem.2015.08.014","article-title":"Therapeutic Implications of Cellular Heterogeneity and Plasticity in Breast Cancer","volume":"17","author":"Brooks","year":"2015","journal-title":"Cell Stem Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/s12943-025-02265-2","article-title":"Cancer stem cells and niches: Challenges in immunotherapy resistance","volume":"24","author":"Pan","year":"2025","journal-title":"Mol. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5919","DOI":"10.1158\/0008-5472.CAN-21-1337","article-title":"ALDH1A1 Activity in Tumor-Initiating Cells Remodels Myeloid-Derived Suppressor Cells to Promote Breast Cancer Progression","volume":"81","author":"Liu","year":"2021","journal-title":"Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.stem.2017.02.003","article-title":"Targeting BMI1+ Cancer Stem Cells Overcomes Chemoresistance and Inhibits Metastases in Squamous Cell Carcinoma","volume":"20","author":"Chen","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/s41392-025-02290-z","article-title":"Tailoring a novel colorectal cancer stem cell-targeted therapy by inhibiting the SMYD3\/c-MYC axis","volume":"10","author":"Forte","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1186\/s13046-022-02516-w","article-title":"LAMC2 marks a tumor-initiating cell population with an aggressive signature in pancreatic cancer","volume":"41","author":"Cave","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1016\/j.stem.2021.04.011","article-title":"CD276 expression enables squamous cell carcinoma stem cells to evade immune surveillance","volume":"28","author":"Wang","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.stem.2023.12.006","article-title":"Hallmarks of stemness in mammalian tissues","volume":"31","author":"Beumer","year":"2024","journal-title":"Cell Stem Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e001048","DOI":"10.1136\/jitc-2020-001048","article-title":"Malignant cell-specific CXCL14 promotes tumor lymphocyte infiltration in oral cavity squamous cell carcinoma","volume":"8","author":"Parikh","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.ccell.2023.02.016","article-title":"The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth","volume":"41","author":"Joyce","year":"2023","journal-title":"Cancer Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s12964-020-0530-4","article-title":"Tumor microenvironment complexity and therapeutic implications at a glance","volume":"18","author":"Baghban","year":"2020","journal-title":"Cell Commun. Signal"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.tibs.2023.03.004","article-title":"The metabolic cross-talk between cancer and T cells","volume":"48","author":"Lucianer","year":"2023","journal-title":"Trends Biochem. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1038\/s41419-023-06119-x","article-title":"Exploring the crosstalk between endothelial cells, immune cells, and immune checkpoints in the tumor microenvironment: New insights and therapeutic implications","volume":"14","author":"Fang","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/s12943-021-01428-1","article-title":"Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: New findings and future perspectives","volume":"20","author":"Mao","year":"2021","journal-title":"Mol. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1038\/s41467-024-46504-4","article-title":"Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas","volume":"15","author":"Broz","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9678","DOI":"10.1038\/s41467-024-53908-9","article-title":"Cancer-associated fibroblast subtypes modulate the tumor-immune microenvironment and are associated with skin cancer malignancy","volume":"15","author":"Forsthuber","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1172\/JCI41004","article-title":"The therapeutic promise of the cancer stem cell concept","volume":"120","author":"Frank","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/cr.2009.138","article-title":"Heterogeneity and plasticity of T helper cells","volume":"20","author":"Zhu","year":"2010","journal-title":"Cell Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s40364-020-00228-x","article-title":"Roles of IFN-gamma in tumor progression and regression: A review","volume":"8","author":"Jorgovanovic","year":"2020","journal-title":"Biomark. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/s41417-020-0183-x","article-title":"Revisiting the role of CD4+ T cells in cancer immunotherapy-new insights into old paradigms","volume":"28","author":"Tay","year":"2021","journal-title":"Cancer Gene Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/35105024","article-title":"T-cell regulation by CD28 and CTLA-4","volume":"1","author":"Alegre","year":"2001","journal-title":"Nat. Rev. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1126\/science.aav7062","article-title":"Restriction of PD-1 function by cis-PD-L1\/CD80 interactions is required for optimal T cell responses","volume":"364","author":"Sugiura","year":"2019","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1146\/annurev.immunol.21.120601.141036","article-title":"Molecular interactions mediating T cell antigen recognition","volume":"21","author":"Davis","year":"2003","journal-title":"Annu. Rev. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1016\/j.cell.2019.03.025","article-title":"Adaptive Immune Resistance Emerges from Tumor-Initiating Stem Cells","volume":"177","author":"Miao","year":"2019","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2356","DOI":"10.1093\/annonc\/mdr620","article-title":"Phase II trial of galiximab (anti-CD80 monoclonal antibody) plus rituximab (CALGB 50402): Follicular Lymphoma International Prognostic Index (FLIPI) score is predictive of upfront immunotherapy responsiveness","volume":"23","author":"Czuczman","year":"2012","journal-title":"Ann. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.3109\/10428194.2012.744453","article-title":"The anti-CD80 primatized monoclonal antibody, galiximab, is well-tolerated but has limited activity in relapsed Hodgkin lymphoma: Cancer and Leukemia Group B 50602 (Alliance)","volume":"54","author":"Smith","year":"2013","journal-title":"Leuk Lymphoma"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.immuni.2007.05.016","article-title":"Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses","volume":"27","author":"Butte","year":"2007","journal-title":"Immunity"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e2205085120","DOI":"10.1073\/pnas.2205085120","article-title":"Blockade of trans PD-L1 interaction with CD80 augments antitumor immunity","volume":"120","author":"Zhang","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1158\/2326-6066.CIR-17-0026","article-title":"Soluble CD80 Protein Delays Tumor Growth and Promotes Tumor-Infiltrating Lymphocytes","volume":"6","author":"Horn","year":"2018","journal-title":"Cancer Immunol. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1038\/s41467-022-29286-5","article-title":"The engineered CD80 variant fusion therapeutic davoceticept combines checkpoint antagonism with conditional CD28 costimulation for anti-tumor immunity","volume":"13","author":"Maurer","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e2023739118","DOI":"10.1073\/pnas.2023739118","article-title":"Treg-expressed CTLA-4 depletes CD80\/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells","volume":"118","author":"Tekguc","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1093\/annonc\/mdm114","article-title":"A phase I\/II study of galiximab (an anti-CD80 monoclonal antibody) in combination with rituximab for relapsed or refractory, follicular lymphoma","volume":"18","author":"Leonard","year":"2007","journal-title":"Ann. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13045-025-01769-0","article-title":"Challenges and strategies in clinical applications of CAR-T therapy for autoimmune diseases","volume":"19","author":"Chen","year":"2025","journal-title":"J. Hematol. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/s13045-025-01759-2","article-title":"In vivo CAR cell therapy: From bench to bedside","volume":"18","author":"Xu","year":"2025","journal-title":"J. Hematol. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/s13045-025-01760-9","article-title":"Emerging advances in CAR-T therapy for solid tumors: Latest clinical trial updates from 2025 ASCO annual meeting","volume":"18","author":"Li","year":"2025","journal-title":"J. Hematol. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1016\/j.ccell.2025.09.013","article-title":"Engineered natural killer cells for cancer therapy","volume":"43","author":"Rezvani","year":"2025","journal-title":"Cancer Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1186\/s12943-025-02386-8","article-title":"Advancing CAR-based cell therapies for solid tumours: Challenges, therapeutic strategies, and perspectives","volume":"24","author":"Azeez","year":"2025","journal-title":"Mol. Cancer"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/3\/266\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T05:18:22Z","timestamp":1769923102000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/3\/266"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,30]]},"references-count":50,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["cells15030266"],"URL":"https:\/\/doi.org\/10.3390\/cells15030266","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,30]]}}}