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Here, we investigated whether the intrinsic conformational stability of target autoantigens regulates the epitope propensity of tumor\u2010associated autoantibodies in non\u2010small cell lung cancer. Using a dual\u2010antigen Luminex bead\u2010based assay that presents each autoantigen in both native and\n                    <jats:italic>S<\/jats:italic>\n                    \u2010cationized denatured forms, we directly compared IgG autoantibody reactivity toward conformational and linear epitopes across 11 autoantigens. Intrinsically disordered aggregation\u2010prone autoantigens, including cancer\/testis antigens, NY\u2010ESO\u20101, and XAGE\u20101b, predominantly elicit linear epitope\u2010directed responses, whereas thermodynamically stable soluble autoantigens generally drive conformational epitope recognition. Intriguingly, for autoantigens harboring both ordered and disordered segments, the immune response is strictly guided by domain\u2010specific biophysics: while p53\u2010specific antibodies preferentially target their flanking disordered regions, the Wilms' tumor protein 1 exceptionally drives conformational recognition directed toward its structured zinc\u2010finger domains. Recombinant solubility in\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    broadly correlated with epitope class across all 11 autoantigens, confirming that prokaryotic folding efficiency generally reflects intrinsic conformational stability in vivo for autonomously folding monomeric cytosolic proteins. Independent computational validation was provided by the concordance between the experimental solubility ratios and AlphaFold3\u2010derived Rosetta energy unit\/solvent\u2010accessible surface area values, demonstrating the convergence of thermodynamic estimates and patient\u2010derived immune data within a unifying biophysical framework. These findings establish that the autoantibody epitope propensity is closely associated with the thermodynamic stability of the target autoantigen and provide a rational basis for tailoring antigen preparation strategies for autoantibody\u2010based cancer diagnosis.\n                  <\/jats:p>","DOI":"10.1002\/pro.70808","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T11:08:51Z","timestamp":1790161731000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Conformational stability and domain\u2010specific structural features of tumor autoantigens regulate autoantibody epitope propensity"],"prefix":"10.1002","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7079-3984","authenticated-orcid":false,"given":"Ai","family":"Miyamoto","sequence":"first","affiliation":[{"name":"Graduate School of Interdisciplinary Science and Engineering in Health Systems Okayama University  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rika","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Graduate School of Interdisciplinary Science and Engineering in Health Systems Okayama University  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryui","family":"Sakaguchi","sequence":"additional","affiliation":[{"name":"Graduate School of Interdisciplinary Science and Engineering in Health Systems Okayama University  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rikako","family":"Kutsuma","sequence":"additional","affiliation":[{"name":"Graduate School of Interdisciplinary Science and Engineering in Health Systems Okayama University  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeru","family":"Mori","sequence":"additional","affiliation":[{"name":"Graduate School of Interdisciplinary Science and Engineering in Health Systems Okayama University  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirei","family":"Masui","sequence":"additional","affiliation":[{"name":"Graduate School of Interdisciplinary Science and Engineering in Health Systems Okayama University  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2552-2794","authenticated-orcid":false,"given":"Tomoko","family":"Honjo","sequence":"additional","affiliation":[{"name":"Graduate School of Interdisciplinary Science and Engineering in Health Systems Okayama University  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Midori","family":"Futami","sequence":"additional","affiliation":[{"name":"Department of Bioscience, Faculty of Life Science Okayama University of Science  Okayama 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