Targeting splenic myeloid cells synergizes with CD47 blockade to inhibit postsurgical tumor recurrence and metastasis.

Cancer recurrence and metastasis remain the major causes of postoperative mortality in solid tumors. Although depletion of tumor-associated myeloid cells shows antitumor efficacy in mice, clinical benefits remain limited due to compensatory mechanisms. The spleen serves as an extramedullary reservoir that continuously supplies myeloid cells supporting tumor progression. Reactivating antitumor immunity by reprogramming splenic myeloid cells thus represents a promising yet underexplored strategy. Using an orthotopic breast cancer model, we revealed that tumor progression reshapes the splenic immune microenvironment, increasing myeloid cells with MDSC-like reprogramming. We developed a spleen-targeted nanosystem (MDP@AE-lip) integrating apolipoprotein, erythrocyte membranes, and PLGA to achieve efficient splenic accumulation and immune cell engagement within the splenic microenvironment. This system induces trained immunity through MDP-mediated epigenetic and metabolic remodeling of splenic myeloid cells. Combined with anti-CD47 (aCD47) therapy, MDP@AE-lip synergistically enhances innate and adaptive antitumor responses, reducing postoperative recurrence by 60% and delaying metastasis. These findings establish splenic-associated immune activation as a crucial therapeutic avenue for preventing tumor recurrence and metastasis, offering strong potential for clinical translation.