{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:06:24Z","timestamp":1792785984815,"version":"4.5.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T00:00:00Z","timestamp":1759449600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Institutional Research","award":["IRG-16-124-37"],"award-info":[{"award-number":["IRG-16-124-37"]}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Phi Beta Psi Cancer Research"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["K22CA212030"],"award-info":[{"award-number":["K22CA212030"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["T32CA009213"],"award-info":[{"award-number":["T32CA009213"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA274857"],"award-info":[{"award-number":["R01CA274857"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental Craniofacial Research","doi-asserted-by":"crossref","award":["5F31DE032263"],"award-info":[{"award-number":["5F31DE032263"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["T32AG058503"],"award-info":[{"award-number":["T32AG058503"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Head and neck squamous cell carcinoma (HNSCC) constitutes 90% of head and neck cancers. HNSCC development is linked to chronic inflammation, while established HNSCC tumors are often immune suppressive. However, both occur through mechanisms that are not fully understood. The cytosolic double-stranded DNA sensor absent in melanoma 2 (AIM2) is an inflammasome-forming protein that also has inflammasome-distinct roles in restricting tumorigenesis by limited PI3K signaling. Here, we used an experimental mouse model of HNSCC, involving treatment of wild-type (WT) and Aim2\u2212\/\u2212 mice with the carcinogen 4NQO in drinking water. Compared with WT mice, 4NQO-treated Aim2\u2212\/\u2212 mice exhibited larger tumors and increased tissue dysplasia. 4NQO-treated WT and Aim2\u2212\/\u2212 mice displayed similar tongue Il6, Tnf, Il1b, Il12, and Il10 expression and no consistent differences in PI3K or inflammasome activation, suggesting AIM2 may not regulate these factors during HNSCC. Instead, Ifng and Irf1 was elevated in 4NQO-treated Aim2\u2212\/\u2212 mice, suggesting that AIM2 restricts IFN-\u03b3. In line with this, RNA sequencing of total tongue RNA from 4NQO-treated mice revealed that Aim2\u2212\/\u2212 mice had enhanced expression of genes related to the major histocompatibility complex protein complex, cell killing, and T cell activation compared with WT mice. We also observed increased macrophage infiltration into the tongue epithelium of 4NQO-treated Aim2\u2212\/\u2212 mice and an increased M1:M2 macrophage ratio. Using Aim2\u2212\/\u2212\/Rag1\u2212\/\u2212 double-deficient animals, we found that the adaptive immune compartment was necessary for the enhanced tumorigenesis during AIM2 deficiency. These findings suggest that AIM2 limits the progression of oral tumor development partially through regulating IFN-\u03b3 and adaptive immune responses.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf224","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T14:52:20Z","timestamp":1759503140000},"page":"3565-3578","source":"Crossref","is-referenced-by-count":2,"title":["Impact of absent in melanoma 2 on head and neck squamous cell carcinoma development"],"prefix":"10.1093","volume":"214","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7221-4329","authenticated-orcid":false,"given":"Dakota M","family":"Reinartz","sequence":"first","affiliation":[{"name":"Department of Immunobiology, University of Arizona , Tucson, AZ 85724,","place":["United States"]},{"name":"University of Arizona Cancer Center , Tucson, AZ 85724,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente","family":"Escamilla-Rivera","sequence":"additional","affiliation":[{"name":"University of Arizona Cancer Center , Tucson, AZ 85724,","place":["United States"]},{"name":"Department of Otolaryngology \u2013 Head and Neck Surgery, University of Arizona , Tucson, AZ 85724,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manlin","family":"Shao","sequence":"additional","affiliation":[{"name":"University of Arizona Cancer Center , Tucson, AZ 85724,","place":["United States"]},{"name":"Cancer Biology Graduate Interdisciplinary Program, University of Arizona , Tucson, AZ 85724,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0091-0982","authenticated-orcid":false,"given":"Stephanie L","family":"Tribble","sequence":"additional","affiliation":[{"name":"University of Arizona Cancer Center , Tucson, AZ 85724,","place":["United States"]},{"name":"Department of Clinical Translational Sciences, University of Arizona , Tucson, AZ 85724,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Caulin","sequence":"additional","affiliation":[{"name":"University of Arizona Cancer Center , Tucson, AZ 85724,","place":["United States"]},{"name":"Department of Otolaryngology \u2013 Head and Neck Surgery, University of Arizona , Tucson, AZ 85724,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin E","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, University of Arizona , Tucson, AZ 85724,","place":["United States"]},{"name":"University of Arizona Cancer Center , Tucson, AZ 85724,","place":["United States"]},{"name":"Cancer Biology Graduate Interdisciplinary Program, University of Arizona , Tucson, AZ 85724,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,10,3]]},"reference":[{"key":"2025122315372404000_vkaf224-B1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"2025122315372404000_vkaf224-B2","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1038\/s41415-022-5166-x","article-title":"Reviewing the epidemiology of head and neck cancer: definitions, trends and risk factors","volume":"233","author":"Gormley","year":"2022","journal-title":"Br Dent J"},{"key":"2025122315372404000_vkaf224-B3","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1093\/jnci\/80.15.1237","article-title":"Dietary factors in oral and pharyngeal cancer","volume":"80","author":"McLaughlin","year":"1988","journal-title":"J Natl Cancer Inst"},{"key":"2025122315372404000_vkaf224-B4","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1016\/S1470-2045(10)70017-6","article-title":"HPV-associated head and neck cancer: a virus-related cancer epidemic","volume":"11","author":"Marur","year":"2010","journal-title":"Lancet Oncol"},{"key":"2025122315372404000_vkaf224-B5","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1158\/2159-8290.CD-13-0103","article-title":"Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers","volume":"3","author":"Lui","year":"2013","journal-title":"Cancer Discov"},{"key":"2025122315372404000_vkaf224-B6","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1016\/j.cell.2010.01.025","article-title":"Immunity, inflammation, and cancer","volume":"140","author":"Grivennikov","year":"2010","journal-title":"Cell"},{"key":"2025122315372404000_vkaf224-B7","doi-asserted-by":"publisher","first-page":"4301","DOI":"10.2147\/JIR.S428358","article-title":"The role of inflammation-associated factors in head and neck squamous cell carcinoma","volume":"16","author":"Li","year":"2023","journal-title":"J Inflamm Res"},{"key":"2025122315372404000_vkaf224-B8","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1038\/s41392-021-00687-0","article-title":"Pattern recognition receptors in health and diseases","volume":"6","author":"Li","year":"2021","journal-title":"Signal Transduct Target Ther"},{"key":"2025122315372404000_vkaf224-B9","doi-asserted-by":"publisher","first-page":"3105","DOI":"10.1158\/0008-5472.CAN-08-3838","article-title":"Triggering of Toll-like receptor 4 expressed on human head and neck squamous cell carcinoma promotes tumor development and protects the tumor from immune attack","volume":"69","author":"Szczepanski","year":"2009","journal-title":"Cancer Res"},{"key":"2025122315372404000_vkaf224-B10","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.oraloncology.2014.08.017","article-title":"Predictive role of Toll-like receptors 2, 4, and 9 in oral tongue squamous cell carcinoma","volume":"51","author":"Makinen","year":"2015","journal-title":"Oral Oncol"},{"key":"2025122315372404000_vkaf224-B11","doi-asserted-by":"publisher","first-page":"1647","DOI":"10.1007\/s00262-022-03357-4","article-title":"NLRP3 in tumor-associated macrophages predicts a poor prognosis and promotes tumor growth in head and neck squamous cell carcinoma","volume":"72","author":"Chen","year":"2023","journal-title":"Cancer Immunol Immunother"},{"key":"2025122315372404000_vkaf224-B12","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1038\/s41590-021-00886-5","article-title":"NLRP3 inflammasome in cancer and metabolic diseases","volume":"22","author":"Sharma","year":"2021","journal-title":"Nat Immunol"},{"key":"2025122315372404000_vkaf224-B13","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1002\/jcp.24816","article-title":"IL-1beta promotes malignant transformation and tumor aggressiveness in oral cancer","volume":"230","author":"Lee","year":"2015","journal-title":"J Cell Physiol"},{"key":"2025122315372404000_vkaf224-B14","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1038\/nature07725","article-title":"AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC","volume":"458","author":"Hornung","year":"2009","journal-title":"Nature"},{"key":"2025122315372404000_vkaf224-B15","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1038\/nm.3908","article-title":"Inflammasome-independent role of AIM2 in suppressing colon tumorigenesis via DNA-PK and Akt","volume":"21","author":"Wilson","year":"2015","journal-title":"Nat Med"},{"key":"2025122315372404000_vkaf224-B16","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/s12967-023-04825-w","article-title":"AIM2 promotes irradiation resistance, migration ability and PD-L1 expression through STAT1\/NF-kappaB activation in oral squamous cell carcinoma","volume":"22","author":"Chiu","year":"2024","journal-title":"J Transl Med"},{"key":"2025122315372404000_vkaf224-B17","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1158\/1940-6207.CAPR-09-0058","article-title":"Chemical carcinogenesis models for evaluating molecular-targeted prevention and treatment of oral cancer","volume":"2","author":"Vitale-Cross","year":"2009","journal-title":"Cancer Prev Res (Phila)"},{"key":"2025122315372404000_vkaf224-B18","doi-asserted-by":"publisher","first-page":"4964","DOI":"10.1158\/1078-0432.CCR-07-1041","article-title":"Dissecting the Akt\/mammalian target of rapamycin signaling network: emerging results from the head and neck cancer tissue array initiative","volume":"13","author":"Molinolo","year":"2007","journal-title":"Clin Cancer Res"},{"key":"2025122315372404000_vkaf224-B19","doi-asserted-by":"publisher","first-page":"24424","DOI":"10.18632\/oncotarget.4420","article-title":"Gene expression profiling signatures for the diagnosis and prevention of oral cavity carcinogenesis-genome-wide analysis using RNA-seq technology","volume":"6","author":"Tang","year":"2015","journal-title":"Oncotarget"},{"key":"2025122315372404000_vkaf224-B20","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1038\/s41586-021-03231-w","article-title":"AIM2 in regulatory T cells restrains autoimmune diseases","volume":"591","author":"Chou","year":"2021","journal-title":"Nature"},{"key":"2025122315372404000_vkaf224-B21","doi-asserted-by":"publisher","first-page":"2230","DOI":"10.3390\/ijms23042230","article-title":"Absent in melanoma 2 (AIM2) regulates the stability of regulatory T cells","volume":"23","author":"Lozano-Ruiz","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2025122315372404000_vkaf224-B22","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/s41368-022-00197-x","article-title":"Interferon-gamma induces immunosuppression in salivary adenoid cystic carcinoma by regulating programmed death ligand 1 secretion","volume":"14","author":"Fu","year":"2022","journal-title":"Int J Oral Sci"},{"key":"2025122315372404000_vkaf224-B23","doi-asserted-by":"publisher","first-page":"e94035","DOI":"10.1172\/jci.insight.94035","article-title":"Aim2-mediated\/IFN-beta-independent regulation of gastric metaplastic lesions via CD8+ T cells","volume":"5","author":"El-Zaatari","year":"2020","journal-title":"JCI Insight"},{"key":"2025122315372404000_vkaf224-B24","doi-asserted-by":"publisher","first-page":"e007110","DOI":"10.1136\/jitc-2023-007110","article-title":"Polymorphonuclear myeloid-derived suppressor cells and phosphatidylinositol-3 kinase gamma are critical to tobacco-mimicking oral carcinogenesis in mice","volume":"11","author":"Nguyen","year":"2023","journal-title":"J Immunother Cancer"},{"key":"2025122315372404000_vkaf224-B25","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1038\/ni.1864","article-title":"The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses","volume":"11","author":"Rathinam","year":"2010","journal-title":"Nat Immunol"},{"key":"2025122315372404000_vkaf224-B26","doi-asserted-by":"publisher","first-page":"108134","DOI":"10.1016\/j.isci.2023.108134","article-title":"AIM2 promotes T(H)17 cells differentiation by regulating RORgammat transcription activity","volume":"26","author":"Leite","year":"2023","journal-title":"iScience"},{"key":"2025122315372404000_vkaf224-B27","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1089\/jir.2018.0087","article-title":"The interferon-gamma paradox in cancer","volume":"39","author":"Zaidi","year":"2019","journal-title":"J Interferon Cytokine Res"},{"key":"2025122315372404000_vkaf224-B28","doi-asserted-by":"publisher","first-page":"100399","DOI":"10.1016\/j.xcrm.2021.100399","article-title":"Effector T cell responses unleashed by regulatory T cell ablation exacerbate oral squamous cell carcinoma","volume":"2","author":"Chao","year":"2021","journal-title":"Cell Rep Med"},{"key":"2025122315372404000_vkaf224-B29","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1016\/j.ijom.2019.04.004","article-title":"Regulatory T cells and M2-polarized tumour-associated macrophages are associated with the oncogenesis and progression of oral squamous cell carcinoma","volume":"48","author":"Kouketsu","year":"2019","journal-title":"Int J Oral Maxillofac Surg"},{"key":"2025122315372404000_vkaf224-B30","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1002\/1878-0261.12029","article-title":"T-cell immunoglobulin mucin 3 blockade drives an antitumor immune response in head and neck cancer","volume":"11","author":"Liu","year":"2017","journal-title":"Mol Oncol"},{"key":"2025122315372404000_vkaf224-B31","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1158\/1940-6207.CAPR-17-0108","article-title":"PD-1 blockade prevents the development and progression of carcinogen-induced oral premalignant lesions","volume":"10","author":"Wang","year":"2017","journal-title":"Cancer Prev Res (Phila)"},{"key":"2025122315372404000_vkaf224-B32","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1177\/0022034511421200","article-title":"Cigarette smoking and inflammation: cellular and molecular mechanisms","volume":"91","author":"Lee","year":"2012","journal-title":"J Dent Res"},{"key":"2025122315372404000_vkaf224-B33","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1164\/rccm.200202-097OC","article-title":"Tumor necrosis factor-alpha is central to acute cigarette smoke-induced inflammation and connective tissue breakdown","volume":"166","author":"Churg","year":"2002","journal-title":"Am J Respir Crit Care Med"},{"key":"2025122315372404000_vkaf224-B34","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1111\/j.1365-2567.2007.02788.x","article-title":"Cigarette smoke increases Toll-like receptor 4 and modifies lipopolysaccharide-mediated responses in airway epithelial cells","volume":"124","author":"Pace","year":"2008","journal-title":"Immunology"},{"key":"2025122315372404000_vkaf224-B35","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/1465-9921-9-66","article-title":"NF-kappaB mediates the survival of human bronchial epithelial cells exposed to cigarette smoke extract","volume":"9","author":"Liu","year":"2008","journal-title":"Respir Res"},{"key":"2025122315372404000_vkaf224-B36","doi-asserted-by":"publisher","first-page":"5546","DOI":"10.1038\/s41467-019-13471-0","article-title":"Syngeneic animal models of tobacco-associated oral cancer reveal the activity of in situ anti-CTLA-4","volume":"10","author":"Wang","year":"2019","journal-title":"Nat Commun"},{"key":"2025122315372404000_vkaf224-B37","doi-asserted-by":"publisher","first-page":"2997","DOI":"10.1002\/ijc.31827","article-title":"AIM2 deficiency reduces the development of hepatocellular carcinoma in mice","volume":"143","author":"Martinez-Cardona","year":"2018","journal-title":"Intl J Cancer"},{"key":"2025122315372404000_vkaf224-B38","doi-asserted-by":"publisher","first-page":"2396","DOI":"10.3892\/or.2019.7029","article-title":"Low expression of AIM2 combined with high expression of p-STAT3 is associated with poor prognosis in hypopharyngeal squamous cell carcinoma","volume":"41","author":"Li","year":"2019","journal-title":"Oncol Rep"},{"key":"2025122315372404000_vkaf224-B39","doi-asserted-by":"publisher","first-page":"2329","DOI":"10.1158\/1078-0432.CCR-16-0224","article-title":"Dual faces of IFNgamma in cancer progression: a role of PD-L1 induction in the determination of pro- and antitumor immunity","volume":"22","author":"Mandai","year":"2016","journal-title":"Clin Cancer Res"},{"key":"2025122315372404000_vkaf224-B40","first-page":"4020","article-title":"Enhancement of metastatic potential by gamma-interferon","volume":"51","author":"Kelly","year":"1991","journal-title":"Cancer Res"},{"key":"2025122315372404000_vkaf224-B41","doi-asserted-by":"publisher","first-page":"e1080416","DOI":"10.1080\/2162402X.2015.1080416","article-title":"Interferon gamma\/NADPH oxidase defense system in immunity and cancer","volume":"5","author":"Hodny","year":"2016","journal-title":"Oncoimmunology"},{"key":"2025122315372404000_vkaf224-B42","doi-asserted-by":"publisher","first-page":"583084","DOI":"10.3389\/fimmu.2020.583084","article-title":"Tumor-associated macrophages in tumor immunity","volume":"11","author":"Pan","year":"2020","journal-title":"Front Immunol"},{"key":"2025122315372404000_vkaf224-B43","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1016\/j.immuni.2009.09.002","article-title":"Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases","volume":"31","author":"Hu","year":"2009","journal-title":"Immunity"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/214\/12\/3565\/64485170\/vkaf224.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/214\/12\/3565\/64485170\/vkaf224.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T20:37:41Z","timestamp":1766522261000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/214\/12\/3565\/8272692"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,3]]},"references-count":43,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,10,3]]},"published-print":{"date-parts":[[2025,12,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jimmun\/vkaf224","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,12]]},"published":{"date-parts":[[2025,10,3]]}}}