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The cluster of differentiation 47 (CD47) plays an important role in tumor immune evasion. CD47 is a highly glycosylated protein, however, the mechanisms governing CD47 glycosylation and its potential role in immunosuppression are unclear. Therefore, this study aimed to evaluate the function of CD47 glycosylation in bladder cancer.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Western blotting, immunohistochemistry, and flow cytometry were used to measure protein expression, protein\u2010protein interactions, and phagocytosis in bladder cancer. A murine model was employed to investigate the impact of mannosidase alpha class 1B member 1 (MAN1B1) modification of CD47 on anti\u2010phagocytosis in vivo. An\n                      <jats:italic toggle=\"yes\">ex vivo<\/jats:italic>\n                      model, patient\u2010derived tumor\u2010like cell clusters, was used to examine the effect of targeting MAN1B1 on phagocytosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Our research identified that aberrant CD47 glycosylation was responsible for its immunosuppression. The glycosyltransferase MAN1B1 responsible for CD47 glycosylation was highly expressed in bladder cancer. Abnormal activation of extracellular signal\u2010regulated kinase (ERK) was significantly associated with MAN1B1 stability by regulating the interaction between MAN1B1 and the E3 ubiquitin ligase HMG\u2010CoA reductase degradation 1 (HRD1). Mechanistically, abnormally activated ERK stabilized MAN1B1, resulting in the glycosylation of CD47 and facilitating immune evasion by enhancing its interaction with signal\u2010regulatory protein alpha (SIRP\u2010\u03b1). In vitro and in vivo experiments demonstrated that\n                      <jats:italic toggle=\"yes\">MAN1B1<\/jats:italic>\n                      knockout weakened CD47\u2010mediated anti\u2010phagocytosis. MAN1B1 inhibitors promoted phagocytosis without causing anemia, offering a safe alternative to anti\u2010CD47 therapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">This comprehensive analysis uncovered that ERK activation stabilizes MAN1B1 by regulating the interaction between MAN1B1 and HRD1, facilitates immune evasion via CD47 glycosylation, and presents new potential targets and strategies for cancer immunotherapy that do not cause anemia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cac2.70040","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T12:00:12Z","timestamp":1749556812000},"page":"1090-1112","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Targeting MAN1B1 potently enhances bladder cancer antitumor immunity via deglycosylation of CD47"],"prefix":"10.34133","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9957-077X","authenticated-orcid":false,"given":"Jie","family":"Zhang","sequence":"first","affiliation":[{"name":"Sir Run Run Shaw Hospital","place":["Hangzhou, P. R. China"]},{"name":"School of Medicine","place":["Hangzhou, P. R. China"]},{"name":"Zhejiang University","place":["Hangzhou, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5447-8978","authenticated-orcid":false,"given":"Chen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Sir Run Run Shaw Hospital","place":["Hangzhou, P. R. China"]},{"name":"School of Medicine","place":["Hangzhou, P. R. China"]},{"name":"Zhejiang University","place":["Hangzhou, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3288-3661","authenticated-orcid":false,"given":"Ruichen","family":"Zang","sequence":"additional","affiliation":[{"name":"Sir Run Run Shaw Hospital","place":["Hangzhou, P. R. China"]},{"name":"School of Medicine","place":["Hangzhou, P. R. China"]},{"name":"Zhejiang University","place":["Hangzhou, P. R. 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Nat Commun. 2017;8:14802.","journal-title":"Nat Commun"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abg8693"},{"issue":"1","key":"e_1_3_2_12_2","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1186\/s40425-019-0812-9","article-title":"Blocking CD47 efficiently potentiated therapeutic effects of anti\u2010angiogenic therapy in non\u2010small cell lung cancer","volume":"7","author":"Zhang X","year":"2019","unstructured":"Zhang X, Wang Y, Fan J, Chen W, Luan J, Mei X, et\u00a0al. Blocking CD47 efficiently potentiated therapeutic effects of anti\u2010angiogenic therapy in non\u2010small cell lung cancer. 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