{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T23:15:44Z","timestamp":1788477344721,"version":"build-2803163510"},"reference-count":35,"publisher":"SAGE Publications","issue":"9-10","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"Nature and Science Foundation of China","award":["82303625"],"award-info":[{"award-number":["82303625"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2026,5,1]]},"abstract":"<jats:p>\n                    The recent evolution of oncolytic virotherapy has yielded viral platforms with enhanced tumor tropism and expanded engineering flexibility, thereby enabling not only direct oncolysis but also deliberate promotion of antitumor immune responses. Here, we systematically explore multiple insertion sites for calreticulin (CALR) within an oncolytic adenovirus, identifying the most optimal variant that exposes robust CALR on tumor cell membrane and functionally motivates macrophages in addition to directly mediating tumor cell lysis. Mechanistically, this variant incorporates a precise deletion within the\n                    <jats:italic toggle=\"yes\">E1A CR2<\/jats:italic>\n                    domain (920\u2013946 bp), enabling selective replication in retinoblastoma-deficient tumor cells. Furthermore, the\n                    <jats:italic toggle=\"yes\">E3-gp19k<\/jats:italic>\n                    region has been replaced with an exogenous Cytomegalovirus (CMV) promoter to achieve precise regulation of CALR overexpression and diminish systemic toxicity. Functionally, by bulk-RNA-Seq, we demonstrate that oncolytic adenovirus (oAd)-CMV-CALR transfection induces endoplasmic reticulum stress, as evidenced by upregulation of phosphorylated eIF2\u03b1, which facilitates the translocation of CALR to the plasma membrane. Via\n                    <jats:italic toggle=\"yes\">ex vivo<\/jats:italic>\n                    coculture assays, we validate that oAd-CMV-CALR transfection enhances the phagocytic capacity of M2 macrophages and promotes their repolarization toward an M1-like phenotype. These findings are further validated in patient-derived ovarian cancer spheroids, underscoring the translational potential of our approach.\n                    <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                    , oAd-CMV-CALR suppresses Hepa1-6 xenograft growth, boosts CD8\n                    <jats:sup>+<\/jats:sup>\n                    T-cell infiltration, and exhibits favorable safety. Collectively, our findings highlight oAd-CMV-CALR as a potential therapeutic approach to modulate the tumor microenvironment and improve cancer immunotherapy outcomes.\n                  <\/jats:p>","DOI":"10.1177\/10430342261423100","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T11:38:24Z","timestamp":1771501104000},"page":"412-424","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Construct Optimization Enables Oncolytic Virus-Mediated Functional Membrane Localization of Calreticulin and Macrophage Reprogramming"],"prefix":"10.1177","volume":"37","author":[{"given":"Xinyuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"},{"name":"Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengfeng","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"},{"name":"Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"},{"name":"Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Si","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"},{"name":"Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhoutong","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"},{"name":"Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teng","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"},{"name":"Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyuan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"},{"name":"Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science 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