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Upon refeeding, these T cells exit the BM and return to circulation. In solid tumors, fasting-refeeding not only affects the trafficking of CD8+ T cells between tumors and their draining lymph nodes (dLNs); but also modulates the antitumor immune response. In this study, we investigated how metformin\u2019s antitumor responses are affected by repeated fasting-refeeding cycles. Metformin administration combined with weekly 48-hour fasting showed a synergistic antitumor effect, which was abolished by in vivo depletion of CD8+ T cells. Immunohistofluorescence staining showed that fasting reduced CD8+ T cells in tumors and dLNs while increasing their presence in the BM; refeeding reversed this distribution. Refeeding also increased the expression of Ifng, Gzmb, Tnf, and Tbx21 in tumors. Likewise, Cxcr6, Cxcl16, and Vcam1 expression levels were elevated only upon refeeding. Notably, CXCR6 was exclusively expressed on CD62L\u2212 effector memory T cells (TEM). The antitumor effect induced by the combinational therapy was abolished by administration of an anti-VCAM-1 neutralizing antibody. Our findings demonstrate that combining metformin with fasting exerts a synergistic antitumor effect by recruiting CD8+ T cells\u2014relocated to the BM during fasting\u2014back to the tumor during refeeding, facilitated by enhanced VCAM-1 expression on normalized tumor vasculature.<\/jats:p>","DOI":"10.1093\/intimm\/dxaf068","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T12:55:29Z","timestamp":1762865729000},"page":"251-263","source":"Crossref","is-referenced-by-count":0,"title":["Repetitive fasting-refeeding enhances metformin-induced CXCR6+ CD8+ T cell tumor infiltration via VCAM-1 upregulation on normalized vasculature during refeeding"],"prefix":"10.1093","volume":"38","author":[{"given":"Weiyang","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 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