Tumor–host colluding through erythroid progenitor cells: Mechanisms and opportunities

Immunotherapy, particularly immune checkpoint blockade (ICB), has shown great promise in the treatment of cancer and emerged as a beacon of hope for patients who have exhausted traditional therapeutic options. Despite ICB's approval for the treatment of advanced tumors, its efficacy remains limited to a small subset of patients. As a systemic disease, cancer can induce changes in the composition and function of the systemic immune system, and ICB resistance often involves a dialog between the tumor microenvironment (TME) and the systemic immune macroenvironment. While investigations into tumor progression and ICB resistance have largely focused on the TME itself, the alterations in the systemic immune system and immune macroenvironment are still poorly understood. Given the spleen's role as the largest secondary lymphoid organ, its examination and discussion may provide valuable insights into the systemic immune status and TME components. Recent studies have highlighted the importance of the spleen in tumor progression and immunotherapy, particularly in the context of erythroid progenitor cells (EPCs), a significant cell subpopulation. In this review, we discuss the mechanisms and role of splenic extramedullary hematopoiesis (EMH) as an intermediary in tumor-host interactions and explore the mechanism of EPC-TME collusions. We further summarize the progress in EPC-targeting strategies and emphasize the potential for further research into the role and mechanisms of EPCs in tumor progression and treatment, which could have far-reaching implications.