{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:30:56Z","timestamp":1791930656456,"version":"4.3.4"},"reference-count":36,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273261"],"award-info":[{"award-number":["82273261"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University","award":["ZZYJ-202401"],"award-info":[{"award-number":["ZZYJ-202401"]}]},{"DOI":"10.13039\/501100008048","name":"Nanjing University","doi-asserted-by":"publisher","award":["0214\/151130"],"award-info":[{"award-number":["0214\/151130"]}],"id":[{"id":"10.13039\/501100008048","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Practice Innovation Program of Jiangsu Province","award":["KYCX24_0285"],"award-info":[{"award-number":["KYCX24_0285"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,2,5]]},"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The pleiotropic roles of tumor-associated macrophages (TAMs) render them attractive targets in antitumor drug development. CD47\/SIRP\u03b1 (signal regulatory protein alpha) and CD24\/Siglec-10 (sialic acid-binding immunoglobulin-like lectin 10) signaling pathways have been found to suppress macrophage phagocytosis of malignant cells. Systemic blockade of CD47\/SIRP\u03b1 has shown severe side effects. Intratumoral delivery of a CD47 inhibitor by oncolytic viruses (OVs) may circumvent this hurdle.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To identify the characteristics of recombinant adenovirus (AdV)-SIRP\u03b1\/Siglec-10, we conducted CCK8 assay, quantitative PCR, western blot, competitive binding assay, in vitro cytotoxicity assay, ELISA and phagocytosis assay. We investigated the antitumor immune responses of AdV-SIRP\u03b1\/Siglec-10 using flow cytometry, various tumor-bearing mouse models, humanized tumor-bearing mouse models, immune cell depletion, RNA sequencing, and in vitro T cell activation assay.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Here, we developed a novel AdV encoding a fusion protein composed of the extracellular domains of murine or human SIRP\u03b1 and Siglec-10 (SIRP\u03b1\/Siglec-10), termed AdV-mSS or AdV-huSS. The SIRP\u03b1\/Siglec-10 was effectively secreted by cells infected with AdV-mSS and functioned as a dual blocker of CD47 and CD24, thereby significantly enhancing macrophage phagocytosis. In a series of tumor models, including subcutaneous and ascitic H22 hepatocellular carcinoma (HCC), subcutaneous Hepa1-6 HCC, MC38 colorectal carcinoma, and Lewis lung carcinoma, AdV-mSS treatment markedly enhanced antitumor efficacy. Mechanistically, AdV-mSS reprogrammed TAMs toward an antitumor phenotype and enhanced the expression of major histocompatibility complex (MHC)-I\/II, promoting CD8+T\u2009cell proliferation and activation. Depletion of either macrophages or CD8+T cells abrogated the antitumor efficacy of AdV-mSS. Similarly, in a humanized LM3 HCC mouse model, AdV-huSS significantly inhibited tumor growth and prolonged survival.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Dual SIRP\u03b1\/Siglec-10 inhibitor delivered intratumorally by AdV not only reinvigorated the TAM-CD8+T\u2009cell axis but also potentially reduced the risk of off-target effects. Further investigation of AdV-huSS in patients with cancer is warranted in the near future.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2024-010767","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T17:18:37Z","timestamp":1743527917000},"page":"e010767","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["Targeted release of a bispecific fusion protein SIRP\u03b1\/Siglec-10 by oncolytic adenovirus reinvigorates tumor-associated macrophages to improve therapeutic outcomes in solid tumors"],"prefix":"10.1136","volume":"13","author":[{"given":"Yenan","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China"},{"name":"Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, Jiangsu, 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