Understanding both local and systemic immunity is essential to optimizing the effectiveness of immunotherapy. However, the dynamic alterations in systemic immunity during tumor development are yet to be clearly defined. Here, we identified a previously unrecognized connection that bridges the interaction between the spleen and tumor through erythroid progenitor cells (EPCs), which suppress tumor immunity and promote tumor progression. We performed the single-cell RNA-seq and RNA-seq to demonstrate the presence of EPCs and identify the characteristic and an immunomodulatory role of EPCs during tumor progression. These tumor-hijacked EPCs proliferate in situ in spleens and impaired systemic and local antitumor response through the interaction between tumor and spleen. Specifically, the splenic CD45