Metabolic processes and microenvironmental regulation in leukemia

Leukemia, a heterogeneous group of hematologic malignancies, continues to present significant therapeutic challenges owing to persistent issues, such as relapse, drug resistance, and treatment-related toxicity. While traditional research has primarily focused on genetic drivers, there is increasing recognition of the critical roles played by the bone marrow microenvironment (BMME) and metabolic reprogramming in disease pathogenesis. This review systematically elucidates the dynamic interplay between these 2 hallmarks of leukemia. We detailed how leukemia cells rewire their metabolic networks to sustain uncontrolled proliferation, emphasizing aberrant activation of glucose metabolism and dynamic remodeling of lipid metabolism via de novo synthesis, uptake, and oxidation. Additionally, we highlighted a critical dependency on specific amino acids, such as glutamine and serine. We investigated the use of BMME to create a protective niche for leukemia cells. These include supportive functions provided by bone marrow stromal cells via direct contact and paracrine signaling, the establishment of an immunosuppressive environment characterized by T cell and natural killer cell exhaustion, an increase in regulatory populations, and the driving force of chronic inflammatory signaling. Importantly, these processes are interdependent, and a reciprocal relationship exists wherein metabolic byproducts from leukemia cells remodel the BMME while simultaneously enabling this microenvironment to dictate metabolic phenotypes in leukemia cells. Targeting the intricate axis between metabolism and the microenvironment is a promising frontier for the development of novel and effective combination therapies against leukemia.