{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T13:13:15Z","timestamp":1770815595049,"version":"3.50.1"},"reference-count":45,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015509","name":"Missouri Department of Health and Senior Services","doi-asserted-by":"crossref","award":["#AOC23380006"],"award-info":[{"award-number":["#AOC23380006"]}],"id":[{"id":"10.13039\/100015509","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Science Foundation (NSF) Cybersecurity Innovation","award":["OAC-2232889"],"award-info":[{"award-number":["OAC-2232889"]}]},{"name":"National Cancer Institute","award":["1UG3CA290305"],"award-info":[{"award-number":["1UG3CA290305"]}]},{"name":"Joan C. Edwards School of Medicine at Marshall University (MURC), Huntington, West Virginia, US"},{"name":"National Institute of General Medical Sciences of the National Institutes of Health","award":["P20GM103434"],"award-info":[{"award-number":["P20GM103434"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Cancer immunoprevention leverages the immune system\u2019s surveillance mechanisms to mitigate tumor development. Vaccines that constitute a tumor antigen and an immune adjuvant are perceived as immunoprevention modalities. However, relevant tumor antigens are unknown for non-viral cancers, which constitute most human cancers. Our group has recently shown that SA\u20134\u20131BBL, a novel agonist of CD137 receptor, but not antibodies, shows immunoprevention efficacy against various tumors. Advanced bioinformatics analyses of bulk RNA-seq data were conducted to elucidate mechanisms underlying cancer immunoprevention. Mice received subcutaneous injections of SA\u20134\u20131BBL or agonistic 3H3 antibody, and the injection-site tissue (IS) and draining lymph nodes (LN) were analyzed for differential gene expression. SA\u20134\u20131BBL induced a compartmentalized and temporally dynamic immune program characterized by early effector activation at IS and sustained immune regulation in draining LN. K-means clustering of 4564 DEGs identified eight functionally distinct clusters. IS-enriched clusters contained activation genes for CD4+ T and NK cells, including Cd28, Klra1, Cd4, Cd40, and Cd40l, while LN clusters were enriched for regulatory genes (Tnfaip3, Irf5, Col1a2) that ensure immune priming and homeostatic restraint for a balanced response. SA\u20134\u20131BBL generated a more selective and durable activation of adaptive immunity, TCR signaling, Th1\/Th2 differentiation, and NK cytotoxicity. 3H3 activated broader innate inflammatory programs, including Toll-like receptor and neurodegeneration-linked pathways. IMPRes analysis showed that SA\u20134\u20131BBL activates sequential immune-regulatory circuits centered on Stat1, Cd247, and Ifng and modulates the CD151\u2013TGF-\u03b2 axis. These findings demonstrate that SA\u20134\u20131BBL elicits a balanced immune response, ensuring both safety and efficacy in preventing cancer development.<\/jats:p>","DOI":"10.3390\/biom16020252","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T17:20:14Z","timestamp":1770225614000},"page":"252","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Elucidating the Mechanisms of SA\u20134\u20131BBL-Mediated Cancer Immunoprevention Through Advanced Informatics Approaches"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0438-5396","authenticated-orcid":false,"given":"Mohit","family":"Verma","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA"},{"name":"Christopher S. Bond Life Science Center, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1004-2653","authenticated-orcid":false,"given":"Feyza Nur","family":"Arguc","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65201, USA"},{"name":"Department of Pediatrics, NextGen Precision Health Institute, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9972-5850","authenticated-orcid":false,"given":"Mohammad T.","family":"Malik","sequence":"additional","affiliation":[{"name":"Department of Medicine, Envirome Institute, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2720-8288","authenticated-orcid":false,"given":"Pallav","family":"Singh","sequence":"additional","affiliation":[{"name":"MU Institute for Data Science and Informatics, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9677-4010","authenticated-orcid":false,"given":"Sameep","family":"Dhakal","sequence":"additional","affiliation":[{"name":"MU Institute for Data Science and Informatics, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3345-9614","authenticated-orcid":false,"given":"Yen On","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA"},{"name":"Christopher S. Bond Life Science Center, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5998-5764","authenticated-orcid":false,"given":"Manish Sridhar","family":"Immadi","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering and Computer Science, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabin","family":"Dahal","sequence":"additional","affiliation":[{"name":"MU Institute for Data Science and Informatics, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8876-2119","authenticated-orcid":false,"given":"Vahap","family":"Ulker","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65201, USA"},{"name":"Department of Pediatrics, NextGen Precision Health Institute, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8829-3041","authenticated-orcid":false,"given":"Mohammad","family":"Tarique","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65201, USA"},{"name":"Department of Pediatrics, NextGen Precision Health Institute, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4375-9004","authenticated-orcid":false,"given":"Lalit","family":"Batra","sequence":"additional","affiliation":[{"name":"Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, KY 40222, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4312-8798","authenticated-orcid":false,"given":"Esma S.","family":"Yolcu","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65201, USA"},{"name":"Department of Pediatrics, NextGen Precision Health Institute, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1657-9470","authenticated-orcid":false,"given":"Haval","family":"Shirwan","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65201, USA"},{"name":"Department of Pediatrics, NextGen Precision Health Institute, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8944-4924","authenticated-orcid":false,"given":"Trupti","family":"Joshi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA"},{"name":"Christopher S. Bond Life Science Center, University of Missouri, Columbia, MO 65201, USA"},{"name":"MU Institute for Data Science and Informatics, University of Missouri, Columbia, MO 65201, USA"},{"name":"Department of Biomedical Informatics, Biostatistics, and Medical Epidemiology, School of Medicine, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1073\/pnas.86.6.1963","article-title":"cDNA sequences of two inducible T-cell genes","volume":"86","author":"Kwon","year":"1989","journal-title":"Proc. Natl. Acad. Sci. 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