{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:38:20Z","timestamp":1791581900647,"version":"4.3.4"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"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. Cell. Infect. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Adjuvants are critical for enhancing vaccine immunogenicity. The agonists in cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway have demonstrated robust immune activation in preclinical models. Peptide vaccines targeting T cell epitopes of high-risk human papillomavirus (HPV) E6 and E7 represent a promising immunization strategy. To improve immunogenicity, we utilized the STING agonist 2\u20193\u2019-cGAMP as an adjuvant and evaluated its ability to enhance immune responses and antitumor efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The immunogenicity and efficacy of a candidate vaccine, consisting of the HPV16 E7\n                      <jats:sub>43\u201377<\/jats:sub>\n                      peptide adjuvanted with 2\u20193\u2019-cGAMP, were evaluated in established TC-1 tumor transplantation models with different initial tumor sizes (2\u20133 mm and 5\u20136 mm in diameter). Tumor-bearing mice received three weekly peritumoral subcutaneous vaccine doses. The effects on tumor suppression, antigen-specific cytotoxic T lymphocyte (CTL) response induction, and related immune mechanisms were investigated both\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Immunization with the E7\n                      <jats:sub>43\u201377<\/jats:sub>\n                      peptide adjuvanted by 2\u20193\u2019-cGAMP significantly suppressed tumor growth and elicited high levels of Interferon (IFN)-\u03b3 and Granzyme B in CD8\n                      <jats:sup>+<\/jats:sup>\n                      cytotoxic T lymphocytes. The vaccine also enhanced the differentiation of natural killer (NK) cells, dendritic cells (DCs), and M1-type macrophages, reduced Myeloid-derived suppressor cells (MDSCs), and increased INF-\u03b2 levels, as well as promote lymphocyte infiltration and remodeling in tumor immune microenvironment (TME). Mechanistically, 2\u20193\u2019-cGAMP promoted DC maturation, enhanced T cell proliferation and activation, and strengthened antigen-specific CTL responses by activating the STING-TBK1-IRF3 and STING-NF-\u03baB pathways in peptide-loaded DCs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The STING agonist 2\u20193\u2019-cGAMP serves as an effective adjuvant that enhances the therapeutic efficacy of an HPV16 peptide vaccine. These findings indicate its potential as a candidate therapeutic for HPV16 persistent infection and associated malignancies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcimb.2026.1798489","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T05:30:53Z","timestamp":1781760653000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["STING agonist 2\u20193\u2019-cGAMP as an effective adjuvant for HPV16 peptide vaccine enhances anti-tumor immunity in TC-1 mice models"],"prefix":"10.3389","volume":"16","author":[{"given":"Yina","family":"Cun","sequence":"first","affiliation":[{"name":"Department of Immunogenetics, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Kunming, Yunnan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Immunogenetics, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Kunming, Yunnan, China"]},{"name":"School of Life Sciences, Yunnan University","place":["Kunming, Yunnan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Immunogenetics, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Kunming, Yunnan, China"]},{"name":"School of Medical Sciences, Shanxi Medical University","place":["Jinzhong, Shanxi, China"]},{"name":"Institute of Cancer Biology, Shanxi Medical University","place":["Jinzhong, Shanxi, China"]},{"name":"Shanxi Center of Technology Innovation for Biomolecular Imaging & Precision Oncology, Shanxi Medical University","place":["Jinzhong, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinwen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Kunming, Yunnan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Immunogenetics, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Kunming, Yunnan, China"]},{"name":"School of Life Sciences, Yunnan University","place":["Kunming, Yunnan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Immunogenetics, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Kunming, Yunnan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Statistics, West China School of Public Health and West China Fourth Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haocheng","family":"He","sequence":"additional","affiliation":[{"name":"Department of Immunogenetics, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Kunming, Yunnan, China"]},{"name":"School of Life Sciences, Yunnan University","place":["Kunming, Yunnan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Immunogenetics, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Kunming, Yunnan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Yao","sequence":"additional","affiliation":[{"name":"Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Kunming, Yunnan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1038\/nri3921","article-title":"Sting: infection, inflammation and cancer","volume":"15","author":"Barber","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.pcl.2016.11.003","article-title":"Human papillomavirus vaccine update","volume":"64","author":"Blake","year":"2017","journal-title":"Pediatr. Clin. North. Am."},{"key":"B3","doi-asserted-by":"publisher","first-page":"5675","DOI":"10.1021\/acs.jmedchem.1c02197","article-title":"Discovery of MK-1454: a potent cyclic dinucleotide stimulator of interferon genes agonist for the treatment of cancer","volume":"65","author":"Chang","year":"2022","journal-title":"J. Med. Chem."},{"key":"B4","doi-asserted-by":"publisher","first-page":"001906","DOI":"10.1136\/jitc-2020-001906","article-title":"Sting agonist-based treatment promotes vascular normalization and tertiary lymphoid structure formation in the therapeutic melanoma microenvironment","volume":"9","author":"Chelvanambi","year":"2021","journal-title":"J. ImmunoTher. Cancer"},{"key":"B5","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1097\/grf.0000000000000788","article-title":"Human papillomavirus vaccines","volume":"66","author":"Conageski","year":"2023","journal-title":"Clin. Obstet. Gynecol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1016\/j.celrep.2015.04.031","article-title":"Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity","volume":"11","author":"Corrales","year":"2015","journal-title":"Cell Rep."},{"key":"B7","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1016\/s0140-6736(13)60022-7","article-title":"Human papillomavirus and cervical cancer","volume":"382","author":"Crosbie","year":"2013","journal-title":"Lancet"},{"key":"B8","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1038\/s41563-022-01251-z","article-title":"Sting agonist delivery by tumour-penetrating PEG-lipid nanodiscs primes robust anticancer immunity","volume":"21","author":"Dane","year":"2022","journal-title":"Nat. Mater."},{"key":"B9","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1038\/s41577-021-00524-z","article-title":"The cGAS-STING pathway as a therapeutic target in inflammatory diseases","volume":"21","author":"Decout","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1186\/s13027-021-00346-7","article-title":"Co-administration of 2'3'-cGAMP STING activator and CpG-C adjuvants with a mutated form of HPV 16 E7 protein leads to tumor growth inhibition in the mouse model","volume":"16","author":"Dorostkar","year":"2021","journal-title":"Infect. Agent Cancer"},{"key":"B11","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1016\/j.drudis.2019.11.007","article-title":"Bioactive modulators targeting STING adaptor in cGAS-STING pathway","volume":"25","author":"Feng","year":"2020","journal-title":"Drug Discov. Today"},{"key":"B12","doi-asserted-by":"publisher","first-page":"F12","DOI":"10.1016\/j.vaccine.2012.07.055","article-title":"Global burden of human papillomavirus and related diseases","author":"Forman","year":"2012","journal-title":"Vaccine"},{"key":"B13","doi-asserted-by":"publisher","first-page":"283ra52","DOI":"10.1126\/scitranslmed.aaa4306","article-title":"Sting agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade","volume":"7","author":"Fu","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1038\/nature07317","article-title":"Sting is an endoplasmic reticulum adaptor that facilitates innate immune signalling","volume":"455","author":"Ishikawa","year":"2008","journal-title":"Nature"},{"key":"B15","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1186\/s13045-020-00916-z","article-title":"cGAS-STING, an important pathway in cancer immunotherapy","volume":"13","author":"Jiang","year":"2020","journal-title":"J. Hematol. Oncol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1740","DOI":"10.1002\/cmdc.202100068","article-title":"E7766, a macrocycle-bridged stimulator of interferon genes (STING) agonist with potent pan-genotypic activity","volume":"16","author":"Kim","year":"2021","journal-title":"ChemMedChem"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.122857","article-title":"Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances antitumor immunity in murine pancreatic cancer","volume":"3","author":"Kinkead","year":"2018","journal-title":"JCI Insight"},{"key":"B18","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1158\/2159-8290.cd-19-0761","article-title":"The cytosolic DNA-sensing cGAS-STING pathway in cancer","volume":"10","author":"Kwon","year":"2020","journal-title":"Cancer Discov."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1390","DOI":"10.1126\/science.1244040","article-title":"Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects","volume":"341","author":"Li","year":"2013","journal-title":"Science"},{"key":"B20","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1038\/s41422-022-00612-2","article-title":"A novel STING agonist-adjuvanted pan-sarbecovirus vaccine elicits potent and durable neutralizing antibody and T cell responses in mice, rabbits and NHPs","volume":"32","author":"Liu","year":"2022","journal-title":"Cell Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"157","DOI":"10.4049\/jimmunol.202.supp.194.8","article-title":"Type I interferon suppresses tumor growth through activating the STAT3-granzyme B pathway in tumor-infiltrating cytotoxic T lymphocytes","volume":"7","author":"Lu","year":"2019","journal-title":"J. ImmunoTher. Cancer"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2435","DOI":"10.1158\/1078-0432.c.6664583.v3","article-title":"Phase I study of SYNB1891, an engineered E. coli Nissle strain expressing STING agonist, with and without atezolizumab in advanced Malignancies","volume":"29","author":"Luke","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1080\/13543784.2021.2010703","article-title":"HPV-induced cancers: preclinical therapeutic advancements","volume":"31","author":"Messa","year":"2022","journal-title":"Expert Opin. Investig. Drugs"},{"key":"B24","volume-title":"WHO preferred product characteristics for therapeutic HPV vaccines","year":"2024"},{"key":"B25","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1038\/s41573-021-00163-y","article-title":"Emerging concepts in the science of vaccine adjuvants","volume":"20","author":"Pulendran","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"B26","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1038\/s41586-018-0705-y","article-title":"Design of amidobenzimidazole STING receptor agonists with systemic activity","volume":"564","author":"Ramanujulu","year":"2018","journal-title":"Nature"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2025.104721","article-title":"Novel therapeutic strategies for targeting E6 and E7 oncoproteins in cervical cancer","volume":"211","author":"Ranasinghe","year":"2025","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"10685","DOI":"10.2147\/ijn.s477320","article-title":"The role of STING-mediated activation of dendritic cells in cancer immunotherapy","volume":"19","author":"Ribeiro","year":"2024","journal-title":"Int. J. Nanomedicine"},{"key":"B29","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1007\/s10156-012-0485-5","article-title":"Immune responses against human papillomavirus (HPV) infection and evasion of host defense in cervical cancer","volume":"18","author":"Sasagawa","year":"2012","journal-title":"J. Infect. Chemother."},{"key":"B30","doi-asserted-by":"publisher","first-page":"371","DOI":"10.3390\/vaccines13040371","article-title":"Progress update on STING agonists as vaccine adjuvants","volume":"13","author":"Shen","year":"2025","journal-title":"Vaccines (Basel)"},{"key":"B31","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1126\/science.1232458","article-title":"Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway","volume":"339","author":"Sun","year":"2013","journal-title":"Science"},{"key":"B32","doi-asserted-by":"publisher","first-page":"3933","DOI":"10.1038\/s41467-024-47692-9","article-title":"The STING agonist IMSA101 enhances chimeric antigen receptor T cell function by inducing IL-18 secretion","volume":"15","author":"Uslu","year":"2024","journal-title":"Nat. Commun."},{"key":"B33","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1002\/1097-0215(200002)9999:9999<::aid-ijc1119>3.0.co;2-c","article-title":"Natural T-helper immunity against human papillomavirus type 16 (HPV16) E7-derived peptide epitopes in patients with HPV16-positive cervical lesions: identification of 3 human leukocyte antigen class II-restricted epitopes","volume":"91","author":"Van der Burg","year":"2001","journal-title":"Int. J. Cancer"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1016\/j.celrep.2018.04.003","article-title":"STING-activating adjuvants elicit a Th17 immune response and protect against Mycobacterium tuberculosis infection","volume":"23","author":"Van Dis","year":"2018","journal-title":"Cell Rep."},{"key":"B35","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1134\/s0006297919070101","article-title":"Therapeutic vaccines against human papilloma viruses: achievements and prospects","volume":"84","author":"Vonsky","year":"2019","journal-title":"Biochem. (Mosc)"},{"key":"B36","doi-asserted-by":"publisher","first-page":"2183","DOI":"10.1016\/j.jid.2016.05.105","article-title":"Natural STING agonist as an \"ideal\" adjuvant for cutaneous vaccination","volume":"136","author":"Wang","year":"2016","journal-title":"J. Invest. Dermatol."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau0810","article-title":"Pulmonary surfactant-biomimetic nanoparticles potentiate heterosubtypic influenza immunity","volume":"367","author":"Wang","year":"2020","journal-title":"Science"},{"key":"B38","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/s41419-024-06638-1","article-title":"STING agonist diABZI enhances the cytotoxicity of T cell towards cancer cells","volume":"15","author":"Wang","year":"2024","journal-title":"Cell Death Dis."},{"key":"B39","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1186\/s12964-025-02169-0","article-title":"Unveiling the crossroads of STING signaling pathway and metabolic reprogramming: the multifaceted role of the STING in the TME and new prospects in cancer therapies","volume":"23","author":"Wang","year":"2025","journal-title":"Cell. Commun. Signal."},{"key":"B40","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1126\/science.1229963","article-title":"Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA","volume":"339","author":"Wu","year":"2013","journal-title":"Science"},{"key":"B41","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.intimp.2019.01.024","article-title":"Prevention and treatment of cervical cancer by a single administration of human papillomavirus peptide vaccine with CpG oligodeoxynucleotides as an adjuvant in vivo","volume":"69","author":"Yang","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"16260","DOI":"10.1073\/pnas.0805325105","article-title":"Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: implications for vaccines","volume":"105","author":"Zhu","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U.S.A."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2026.1798489\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T05:30:54Z","timestamp":1781760654000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2026.1798489\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,18]]},"references-count":42,"alternative-id":["10.3389\/fcimb.2026.1798489"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2026.1798489","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,18]]},"article-number":"1798489"}}