{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:25:28Z","timestamp":1787163928492,"version":"build-2736575974"},"reference-count":62,"publisher":"National Academy of Sciences","issue":"34","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"MOST | National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2020YFA0803200"],"award-info":[{"award-number":["2020YFA0803200"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82222052 32070710 31930026 92168116"],"award-info":[{"award-number":["82222052 32070710 31930026 92168116"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:p>\n                    Neutrophils display profound functional plasticity within the tumor microenvironment (TME), a key determinant of cancer progression; however, the intrinsic mechanisms safeguarding their antitumor identity remain elusive. Here, we identify the Hippo pathway component Vgll4 as a pivotal guardian of neutrophil functional fate in the TME. While dispensable for homeostatic granulopoiesis, Vgll4 in neutrophils is crucial for restraining tumor growth. Neutrophil-specific ablation of Vgll4 triggers a phenotypic shift toward an immunosuppressive state, accelerating tumor progression. Mechanistically, Vgll4 binds STAT3 and STAT5 in a JAK-dependent manner; loss of Vgll4 reduces SOCS3 expression, a negative regulator of STAT3, thereby unleashing STAT3 hyperactivation while suppressing STAT5, leading to transcriptional reprogramming that establishes an immunosuppressive profile. This regulatory axis operates specifically in tumor-associated neutrophils, as Vgll4 is dispensable for steady-state development but essential within the TME. Consequently, Vgll4-deficient neutrophils remodel the TME by promoting regulatory T cell (Treg) differentiation and impairing CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell effector function. Our findings unveil a noncanonical role for Vgll4 in innate immune regulation and establish the Vgll4-STAT3\/STAT5 axis as a crucial checkpoint in neutrophil polarization, presenting a therapeutic target for cancer immunotherapy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2606983123","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:37:08Z","timestamp":1787161028000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Neutrophil-intrinsic Vgll4 constrains tumorigenesis by preventing a STAT3\/STAT5-driven immunosuppressive switch"],"prefix":"10.1073","volume":"123","author":[{"given":"Lin","family":"Shao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Zhongshan Hospital, Fudan University","place":["Shanghai, 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Medicine, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moubin","family":"Lin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03rc6as71","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0731-6801","authenticated-orcid":false,"given":"Miao","family":"He","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Brain Function and Disorders and Ministry of Education Frontiers Center for Brain Science, Department of Neurobiology, Zhongshan Hospital, Institutes of Brain Science, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfeng","family":"Chen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013q1eq08","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology, School of Basic Medical Sciences, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5441-3922","authenticated-orcid":false,"given":"Zhaocai","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Zhongshan Hospital, Fudan University","place":["Shanghai, China"]},{"name":"Tianfu Jincheng Laboratory","place":["Chengdu, China"]},{"id":[{"id":"https:\/\/ror.org\/059gcgy73","id-type":"ROR","asserted-by":"publisher"}],"name":"Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical 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Zhou Vgll4 Governs Neutrophil identity to restrain a STAT3-Dependent PMN-MDSC switch during tumor progression. National Genomics Data Center. https:\/\/ngdc.cncb.ac.cn\/gsa\/browse\/CRA032015. 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