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CR disruption (CRD), such as shift work, has been associated with increased cancer risk, particularly female breast cancer (BC), yet the mechanisms underlying breast tumorigenesis and immunosuppression resulting from a specific clock gene dysfunction remain unclear. Here, we identify that circadian regulator Period 2 (PER2) is significantly downregulated in BC and correlates with poor prognosis. PER2 functional deficiency mice (\n                    <jats:italic>PAS-B<\/jats:italic>\n                    domain deletion,\n                    <jats:italic>Per2<\/jats:italic>\n                    <jats:sup>m\/m<\/jats:sup>\n                    ) display high susceptibility to DMBA\/MPA-induced breast tumors. Tumor microenvironment (TME) profiling reveals that compared with\n                    <jats:italic>Per2<\/jats:italic>\n                    <jats:sup>wt<\/jats:sup>\n                    tumors induced in\n                    <jats:italic>Per2<\/jats:italic>\n                    <jats:sup>wt<\/jats:sup>\n                    mice,\n                    <jats:italic>Per2<\/jats:italic>\n                    <jats:sup>m\/m<\/jats:sup>\n                    tumors generated in\n                    <jats:italic>Per2<\/jats:italic>\n                    <jats:sup>m\/m<\/jats:sup>\n                    mice show reduced CD8\u207a T cells and M1-like macrophages infiltration and increased Foxp3\n                    <jats:sup>+<\/jats:sup>\n                    Tregs and M2-like macrophages. Of note, reciprocal transplantation of\n                    <jats:italic>Per2<\/jats:italic>\n                    <jats:sup>m\/m<\/jats:sup>\n                    and\n                    <jats:italic>Per2<\/jats:italic>\n                    <jats:sup>wt<\/jats:sup>\n                    tumors into\n                    <jats:italic>Per2<\/jats:italic>\n                    <jats:sup>wt<\/jats:sup>\n                    or\n                    <jats:italic>Per2<\/jats:italic>\n                    <jats:sup>m\/m<\/jats:sup>\n                    mouse hosts reveals that systemic PER2 functional deficiency status not only boosts tumor growth but also promotes immunosuppression in TME. Consistently,\n                    <jats:italic>Per2<\/jats:italic>\n                    knockdown in tumor cells enhances tumor cell proliferation and immune evasion in WT hosts. Mechanistically, PER2 knockdown leads to aberrant CLOCK transactivation, which upregulates the co-expression of HER2 and CD47, thereby leading to tumor aggressive growth with limited macrophage immune checkpoint surveillance. Collectively, our findings suggest that PER2 functional deficiency-driven CLOCK-HER2\/CD47 axis promotes BC susceptibility and tumor immunosuppression, which provides a potential therapeutic target to mitigate CRD-associated BC risk and aggressiveness.\n                  <\/jats:p>","DOI":"10.1038\/s41388-026-03941-3","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T17:01:26Z","timestamp":1786554086000},"page":"4269-4283","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Functional deficiency of circadian regulator PER2 enhances breast cancer susceptibility and progression with immunosuppression"],"prefix":"10.1038","volume":"45","author":[{"given":"Yixin","family":"Duan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aris T.","family":"Alexandrou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0381-1549","authenticated-orcid":false,"given":"Jie","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen S.","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5669-5791","authenticated-orcid":false,"given":"Hongyong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dake","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan I.","family":"Berg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yili","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7178-834X","authenticated-orcid":false,"given":"Loning","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0558-5250","authenticated-orcid":false,"given":"Lunquan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3694-9675","authenticated-orcid":false,"given":"Jian Jian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"3941_CR1","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1038\/s41586-024-08056-x","volume":"635","author":"MP Shahandeh","year":"2024","unstructured":"Shahandeh MP, Abuin L, Lescuyer De Decker L, Cergneux J, Koch R, Nagoshi E, et al. 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