Targeting erythroid progenitor cell metabolism to enhance cancer immunotherapy

While cancer immunotherapy has transformed clinical management for cancer patients, its low response rates remain a critical challenge to be addressed. Tumor immune evasion now extends beyond the tumor microenvironment (TME), as advanced tumors induce extramedullary hematopoiesis (EMH) in the spleen, leading to a substantial expansion of erythroid progenitor cells (EPCs) with potent immunosuppressive capacity. EPCs are typically transient populations in erythroid maturation and differentiation; however, under tumor burden, they undergo profound metabolic reprogramming that exacerbates their immunosuppressive effects. This review examines the role and mechanisms of tumor-hijacked metabolic reprogramming in EPCs and provides strategies for targeting this reprogramming to potentiate cancer immunotherapy. In particular, we synthesize the metabolic interplay between EPCs, tumor cells, and immune cells, integrating EPC metabolic reprogramming with established concepts of tumor cell metabolism and immunometabolism. Furthermore, this review outlines future directions for the field, including multi-modal approaches to decipher the mechanisms of EPC metabolic reprogramming, biomarker development, and metabolism-based targeted therapies, all aimed at improving survival and prognosis for cancer patients.