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They express the immune checkpoint molecule PD-L1 and can induce T cell exhaustion, thereby promoting immunosuppression. In this study, we investigated whether tumor-derived\n                    <jats:italic>Cldn7<\/jats:italic>\n                    deficiency could recruit polymorphonuclear neutrophils (PMNs), induce their metabolic reprogramming, and consequently drive their transition toward a pro-tumor phenotype, leading to the establishment of an immunosuppressive tumor microenvironment (TME). Using single-cell RNA sequencing, clinical sample validation, and both in vivo and in vitro experiments, we found that\n                    <jats:italic>Cldn7<\/jats:italic>\n                    deficiency in colorectal cancer (CRC) results in a tumor microenvironment characterized by significantly increased infiltration of CD11b\u207a Ly6G\u207a neutrophils. This is accompanied by neutrophil metabolic reprogramming that facilitates their phenotypic shift toward a tumor-promoting state, which in turn suppresses the cytotoxic function of CD8\u207a T cells and contributes to the formation of an immunosuppressive TME, thereby accelerating CRC progression. Mechanistically,\n                    <jats:italic>Cldn7<\/jats:italic>\n                    deficiency indirectly activates the NF-\u03baB signaling pathway, leading to elevated secretion of chemokines such as CXCL1 that are responsible for PMN recruitment. Inhibition of the NF-\u03baB\/CXCL1 axis reduces PMN infiltration, decreases PD-L1 expression on neutrophils, suppresses neutrophil glycolysis and histone lactylation, reverses the exhausted phenotype of CD8\u207a T cells, thereby mitigating the immunosuppressive microenvironment. Furthermore, overexpression of\n                    <jats:italic>Cldn7<\/jats:italic>\n                    enhances the efficacy of immune checkpoint blockade (ICB) therapy.Collectively, our findings indicate that\n                    <jats:italic>Cldn7<\/jats:italic>\n                    deficiency not only contributes to immune evasion and malignant progression in CRC but also plays a critical role in immune modulation. Targeting PMN metabolic reprogramming and immunosuppressive function associated with\n                    <jats:italic>Cldn7<\/jats:italic>\n                    loss may offer a promising strategy to improve the therapeutic efficacy of immunotherapy in CRC.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-08064-3","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T13:41:39Z","timestamp":1760622099000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Claudin-7 deficiency induces metabolic reprogramming of neutrophils in the colorectal cancer microenvironment"],"prefix":"10.1038","volume":"16","author":[{"given":"Xiaoqing","family":"Liang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dajin","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songyun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianbo","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengdi","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7350-8508","authenticated-orcid":false,"given":"Lei","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"8064_CR1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s13304-016-0359-y","volume":"68","author":"P Favoriti","year":"2016","unstructured":"Favoriti P, Carbone G, Greco M, Pirozzi F, Pirozzi REM, Corcione F. 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