Implications of metabolism-driven myeloid dysfunctions in cancer therapy

Immune homeostasis is maintained by an adequate balance of myeloid and lymphoid responses.In chronic inflammatory states,including cancer,this balance is lost due to dramatic expansion of myeloid progenitors that fail to mature to functional inflammatory neutrophils,macrophages,and dendritic cells(DCs),thus giving rise to a decline in the antitumor effector lymphoid response.Cancer-related inflammation orchestrates the production of hematopoietic growth factors and cytokines that perpetuate recruitment and activation of myeloid precursors,resulting in unresolved and chronic inflammation.This pathologic inflammation creates profound alterations in the intrinsic cellular metabolism of the myeloid progenitor pool,which is amplified by competition for essential nutrients and by hypoxia-induced metabolic rewiring at the tumor site.Therefore,persistent myelopoiesis and metabolic dysfunctions contribute to the development of cancer,as well as to the severity of a broad range of diseases,including metabolic syndrome and autoimmune and infectious diseases.The aims of this review are to(1)define the metabolic networks implicated in aberrant myelopoiesis observed in cancer patients,(2)discuss the mechanisms underlying these clinical manifestations and the impact of metabolic perturbations on clinical outcomes,and(3)explore new biomarkers and therapeutic strategies to restore immunometabolism and differentiation of myeloid cells towards an effector phenotype to increase host antitumor immunity.We propose that the profound metabolic alterations and associated transcriptional changes triggered by chronic and overactivated immune responses in myeloid cells represent critical factors influencing the balance between therapeutic efficacy and immune-related adverse effects(irAEs)for current therapeutic strategies,including immune checkpoint inhibitor(ICI)therapy.