{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T09:18:31Z","timestamp":1783502311450,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,4]]},"reference-count":91,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T00:00:00Z","timestamp":1783123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health","award":["1ZIABC012091"],"award-info":[{"award-number":["1ZIABC012091"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Hypermutational processes, including those driven by the APOBEC3 family of cytidine deaminases, generate abundant neoantigens yet give rise to tumors that evade immune recognition. Here, using multi-omics analyses followed by functional validation, we identified a tumor-intrinsic immune-cloaking mechanism in neoantigen-rich epithelial cancers, characterized by coordinated suppression of antigen presentation, immune-recruiting cytokines and immune-checkpoint programs. In bladder cancer, genome-wide copy-number analysis identified recurrent 1q23.3 amplification as a genomic feature of a neoantigen-high\/CD8-low tumor state. Within this locus,\n                  <jats:italic>NECTIN4<\/jats:italic>\n                  emerged as the dominant candidate effector, outperforming extrachromosomal DNA status as a predictor of immune\u2013neoantigen discordance. Similar associations were observed across breast and lung cancers. Functional studies demonstrated that NECTIN4 was sufficient to establish a T-cell-poor tumor microenvironment and confer resistance to PD-1 blockade in immunocompetent mice. Mechanistically, NECTIN4 engaged a DDR1\u2013SHP2 axis that suppressed STAT1 phosphorylation, silencing tumor-cell immune-engagement programs. NECTIN4 blockade restored STAT1 activity and reduced tumor growth, indicating that the cloaked state is pharmacologically reversible. Mutational signature, breakpoint motif, timing and clonality analyses, together with\n                  <jats:italic>APOBEC3B<\/jats:italic>\n                  expression and germline genetic evidence, linked APOBEC3-mediated mutagenesis to recurrent 1q23.3 amplification encompassing\n                  <jats:italic>NECTIN4<\/jats:italic>\n                  . These findings reveal how neoantigen-generating mutational processes can be coupled to structural genome evolution to enable tumor-intrinsic immune cloaking through a therapeutically targetable NECTIN4\u2013DDR1\u2013SHP2 axis.\n                <\/jats:p>","DOI":"10.64898\/2026.07.01.735125","type":"posted-content","created":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T15:20:14Z","timestamp":1783178414000},"source":"Crossref","is-referenced-by-count":0,"title":["APOBEC3-driven neoantigen-rich cancers co-opt 1q23.3 amplification for tumor-intrinsic immune cloaking"],"prefix":"10.64898","author":[{"given":"Dhanusha","family":"Yesudhas","sequence":"first","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bilal","family":"Lone","sequence":"additional","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ecem","family":"Unal","sequence":"additional","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arup","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayse G.","family":"Keskus","sequence":"additional","affiliation":[{"name":"Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaimie","family":"Ryou","sequence":"additional","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Butler","sequence":"additional","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania Colon","family":"Aquino","sequence":"additional","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abbas","family":"Yousefi-Rad","sequence":"additional","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiming","family":"Yang","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Mass Spectrometry Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa M","family":"Jenkins","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Mass Spectrometry Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raju","family":"Chelluri","sequence":"additional","affiliation":[{"name":"Urological Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elias BA","family":"Chandran","sequence":"additional","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir A. 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