{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T07:02:29Z","timestamp":1780470149005,"version":"3.54.1"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"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>Cancer immunotherapy faces persistent limitations due to its reliance on single-signal therapeutic architectures, which are vulnerable to antigen loss, off-tumor toxicity, and tumor heterogeneity. A fundamental contributor to therapeutic failure is the generation of biological decision errors \u2014 false-positive activation in normal tissues and false-negative missed recognition in antigen-low tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We propose the Adaptive Anti-Error Biological System (AABS), a conceptual framework designed to improve therapeutic precision through structured multi-signal validation and conditional effector activation. A simplified implementation, AABS-01, is introduced as a trimodular conditional therapeutic model integrating tumor priming, dual-signal AND-gate logic, and conditional effector engagement.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Framework<\/jats:title>\n                    <jats:p>AABS-01 operates through three coordinated layers: (1) a Tumor Priming Layer enhancing antigen visibility through tumor-restricted IFN-\u03b3 conditioning, epigenetic modulation, and TME normalization; (2) a Validation Layer implementing Boolean AND-gate logic requiring simultaneous detection of two independent tumor-associated signals; and (3) an Effector Layer triggering localized immune activation exclusively upon validated dual-signal convergence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Bioinformatic support<\/jats:title>\n                    <jats:p>Analysis of TCGA Pan-Cancer Atlas and GTEx v8 transcriptomic data confirms that four candidate signal pairs (HER2\/MUC4, EGFR\/EpCAM, MSLN\/HER2, PD-L1\/GD2) achieve corrected Tumor Specificity Index (TSI) values of 18.3x to 46.8x across six cancer types, after correction for inter-signal correlation (r = 0.18\u20130.44). A revised probabilistic framework accounting for signal co-regulation demonstrates that AND-gate logic achieves 3\u20138x false-positive rate reduction versus single-signal approaches under empirically observed correlation conditions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>AABS represents a paradigm shift from reactive to decision-based cancer immunotherapy, grounded in established immunological principles including T-cell multi-signal activation and kinetic proofreading. A five-phase experimental roadmap with quantitative endpoints is provided to guide preclinical and translational validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1845119","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T06:06:15Z","timestamp":1780466775000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A conditional multi-signal validation framework for cancer immunotherapy: the adaptive anti-error biological system"],"prefix":"10.3389","volume":"17","author":[{"given":"Emery M.","family":"Kalondero","sequence":"first","affiliation":[{"name":"D\u00e9partement of sciences, Universit\u00e9 Sainte-Anne","place":["Church Point, NS, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: the next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"B2","volume-title":"Cancer. Global health estimates","year":"2022"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar6711","article-title":"CAR T cell immunotherapy for human cancer","volume":"359","author":"June","year":"2018","journal-title":"Science"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar4060","article-title":"Cancer immunotherapy using checkpoint blockade","volume":"359","author":"Ribas","year":"2018","journal-title":"Science"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.cd-12-0548","article-title":"The basic principles of chimeric antigen receptor design","volume":"3","author":"Sadelain","year":"2013","journal-title":"Cancer Discov"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2013.17","article-title":"Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells","volume":"21","author":"Lamers","year":"2011","journal-title":"Mol Ther"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.01.011","article-title":"Precision tumor recognition by T cells with combinatorial antigen-sensing circuits","volume":"164","author":"Roybal","year":"2016","journal-title":"Cell"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1126\/science.aba6527","article-title":"Designed protein logic to target cells with precise combinations of surface antigens","volume":"369","author":"Lajoie","year":"2020","journal-title":"Science"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2103485","article-title":"Overall survival benefit with tebentafusp in metastatic uveal melanoma","volume":"385","author":"Nathan","year":"2021","journal-title":"NEJM"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2926","article-title":"Principles of genetic circuit design","volume":"11","author":"Brophy","year":"2014","journal-title":"Nat Methods"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.71.10.4135","article-title":"Kinetic proofreading: a new mechanism for reducing errors in biosynthetic processes requiring high specificity","volume":"71","author":"Hopfield","year":"1974","journal-title":"PNAS"},{"key":"B12","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.coi.2015.12.007","article-title":"The urgent need to recover MHC class I in cancers for effective immunotherapy","volume":"39","author":"Garrido","year":"2016","journal-title":"Curr Opin Immunol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s12276-018-0191-1","article-title":"Immune checkpoint inhibitors: recent progress and potential biomarkers","volume":"50","author":"Darvin","year":"2018","journal-title":"Exp Mol Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3239","article-title":"The blockade of immune checkpoints in cancer immunotherapy","volume":"12","author":"Pardoll","year":"2012","journal-title":"Nat Rev Cancer"},{"key":"B15","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/s1470-2045(14)71170-2","article-title":"Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor ALL","volume":"16","author":"Topp","year":"2015","journal-title":"Lancet Oncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2016.10.005","article-title":"A synthetic mammalian therapeutic gene circuit for sensing and suppressing inflammation","volume":"25","author":"Smole","year":"2017","journal-title":"Mol Ther"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1604958","article-title":"Mutations associated with acquired resistance to PD-1 blockade in melanoma","volume":"375","author":"Zaretsky","year":"2016","journal-title":"NEJM"},{"key":"B18","doi-asserted-by":"publisher","first-page":"113900","DOI":"10.1016\/j.addr.2021.113900","article-title":"Tumor-targeted cytokine delivery: recent advances and clinical perspectives","volume":"177","author":"Hutmacher","year":"2021","journal-title":"Adv Drug Delivery Rev"},{"key":"B19","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/icb.1975.3","article-title":"A new analysis of allogeneic interactions","volume":"53","author":"Lafferty","year":"1975","journal-title":"Aust J Exp Biol Med Sci"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2017.02.007","article-title":"Mex3a marks a slowly dividing subpopulation of Lgr5+ intestinal stem cells","volume":"20","author":"Barriga","year":"2017","journal-title":"Cell Stem Cell"},{"key":"B21","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/j.cell.2018.03.022","article-title":"Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer","volume":"173","author":"Hoadley","year":"2018","journal-title":"Cell"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan2507","article-title":"A pathology atlas of the human cancer transcriptome","volume":"357","author":"Uhlen","year":"2017","journal-title":"Science"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2017.69","article-title":"Classifying the evolutionary and ecological features of neoplasms","volume":"17","author":"Maley","year":"2017","journal-title":"Nat Rev Cancer"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2016.68.3672","article-title":"Mesothelin immunotherapy for cancer: ready for prime time","volume":"34","author":"Hassan","year":"2016","journal-title":"J Clin Oncol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1845119\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T06:06:17Z","timestamp":1780466777000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1845119\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,3]]},"references-count":24,"alternative-id":["10.3389\/fimmu.2026.1845119"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1845119","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,3]]},"article-number":"1845119"}}