Tumor‐Induced Splenic Remodeling: Mechanisms of Systemic Immunosuppression and Emerging Therapeutic Opportunities

ABSTRACT Despite the transformative impact of cancer immunotherapies such as immune checkpoint blockade, durable clinical responses remain limited. 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‐filtering 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‐tumorigenic immune compartment characterized by pathological extramedullary hematopoiesis, and sustained generation of immunosuppressive cell populations, including myeloid‐derived 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‐induced 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‐induced splenic remodeling as a central yet underappreciated determinant of immunotherapy response and a promising target for next‐generation immunotherapies.