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Increasing evidence indicates that antitumor immunity is governed not only by the tumor microenvironment, but also by systemic immune regulation mediated by peripheral immune organs. Among these, the spleen functions as a central blood\u2010filtering immune hub that integrates immune activation with hematopoietic adaptation. During tumor progression, the spleen undergoes profound remodeling, shifting from a site of immune surveillance to a pro\u2010tumorigenic immune compartment characterized by pathological extramedullary hematopoiesis, and sustained generation of immunosuppressive cell populations, including myeloid\u2010derived suppressor cells. Continuous systemic export of these cells reinforces tumor immune evasion and constrains the efficacy of immune checkpoint blockade. In this review, we summarize current understanding of splenic structure and immunological function, delineate the mechanisms driving tumor\u2010induced splenic remodeling, and examine its role in systemic immunosuppression and resistance to cancer immunotherapy. We further evaluate emerging therapeutic strategies aimed at targeting the spleen, highlighting both their translational potential and key biological barriers. Collectively, this work identifies tumor\u2010induced splenic remodeling as a central yet underappreciated determinant of immunotherapy response and a promising target for next\u2010generation immunotherapies.<\/jats:p>","DOI":"10.1002\/advs.202600027","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T18:45:26Z","timestamp":1774032326000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Tumor\u2010Induced Splenic Remodeling: Mechanisms of Systemic Immunosuppression and Emerging Therapeutic Opportunities"],"prefix":"10.1002","volume":"13","author":[{"given":"Yuehua","family":"Liu","sequence":"first","affiliation":[{"name":"Research Center for Industries of the Future and School of Life Sciences Westlake University  Hangzhou Zhejiang China"},{"name":"Westlake Laboratory of Life Sciences and Biomedicine  Hangzhou Zhejiang 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