{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:50:25Z","timestamp":1790628625025,"version":"4.1.0"},"posted":{"date-parts":[[2026,7,23]]},"group-title":"Cancer Biology","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Maryland Technology Development Corporation"},{"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Cluster of differentiation 47 (CD47) blockade promotes tumor cell phagocytosis; however, transitioning this initial innate immune event into durable anti-cancer adaptive immunity and tumor control remains a critical challenge. To address this translational gap, we have engineered aCD47 \u2013 CpG, a novel immune-stimulating antibody conjugate (ISAC) coupling a CD47-blocking antibody (aCD47) to a Toll-like receptor 9 agonist, unmethylated CpG, to enable synchronized deployment of co-stimulatory signals during tumor engulfment. This ISAC, aCD47-CpG, but not the parent aCD47, reprograms macrophages toward an anti-tumor M1-like phenotype, enhances antigen cross-presentation, and promotes robust CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell priming. We found that systemically administered aCD47-CpG drove macrophage-dependent tumor suppression in a human lymphoma xenograft model. In parallel, the treatment in immunocompetent syngeneic models of lymphoma and highly immunosuppressive triple-negative breast cancer resulted in profound tumor regression, metastasis inhibition, and durable anti-cancer immune memory. These effects were accompanied by remodeling of the immunosuppressive tumor microenvironment toward an immune-permissive state, characterized by M2-to-M1 macrophage repolarization, intratumoral infiltration of cytotoxic and memory T cells, and depletion of regulatory T cells. This spatiotemporally coordinated immunotherapy platform offers a promising strategy to bridge innate and adaptive immunity, thereby advancing the translational potential of CD47-targeted cancer therapies.\n                <\/jats:p>","DOI":"10.64898\/2026.07.22.739359","type":"posted-content","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T13:55:23Z","timestamp":1784814923000},"source":"Crossref","is-referenced-by-count":1,"title":["An immune-stimulating antibody conjugate spatiotemporally targeting CD47 and TLR9 elicits macrophage-dependent tumor clearance and durable anti-cancer adaptive immunity"],"prefix":"10.64898","author":[{"given":"Byoungjae","family":"Kong","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA"},{"name":"Medicine Institute for Neuroscience Discovery (UM-MIND), University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Woo","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiheon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA"},{"name":"Medicine Institute for Neuroscience Discovery (UM-MIND), University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gijung","family":"Kwak","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA"},{"name":"Medicine Institute for Neuroscience Discovery (UM-MIND), University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Soo","family":"Suk","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA"},{"name":"Medicine Institute for Neuroscience Discovery (UM-MIND), University of Maryland School of Medicine, Baltimore, MD 21201, USA"},{"name":"Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"name":"Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026072711401435000_2026.07.22.739359v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2010.04.001"},{"key":"2026072711401435000_2026.07.22.739359v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.07.044"},{"key":"2026072711401435000_2026.07.22.739359v1.3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1121623109"},{"key":"2026072711401435000_2026.07.22.739359v1.4","first-page":"80","article-title":"Macrophage checkpoint blockade: results from initial clinical trials, binding analyses, and CD47-SIRPalpha structure-function","volume":"3","year":"2020","journal-title":"Antib. 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