Immunometabolic Reprogramming in the Bone Marrow Niche: Mechanisms, Plasticity, and Precision Therapeutic Targeting

The bone marrow (BM) microenvironment is increasingly recognized as a dynamic immunometabolic niche that critically governs hematologic malignancies and BM-associated disorders, including acute myeloid leukemia (AML), multiple myeloma, myelodysplastic syndromes (MDS), metastatic infiltration, and aplastic anemia. At the core of this ecosystem, hematopoietic and leukemic stem cells (HSCs/LSCs) undergo profound immunometabolic reprogramming driven by complex interactions with stromal and immune components. Mesenchymal stromal cells (MSCs) enhance mitochondrial fitness and oxidative phosphorylation (OXPHOS) in malignant cells via cysteine supply and mitochondrial transfer, while endothelial cells regulate niche retention and survival through CXCL12 and adhesion molecules such as E-selectin. Adipocytes further support tumor bioenergetics by supplying free fatty acids (FFAs) that fuel fatty acid oxidation (FAO), whereas M2-polarized macrophages reinforce immunosuppressive and metabolic adaptations through arginase-1 activity and FAO-dependent pathways. These coordinated interactions promote a metabolically flexible phenotype characterized by shifts between OXPHOS and glycolysis, activation of FAO and glutamine metabolism, and engagement of one-carbon metabolism, collectively sustaining malignant progression. Concurrently, the BM niche establishes a profoundly immunosuppressive milieu mediated by myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), indoleamine 2,3-dioxygenase 1 (IDO1)-driven kynurenine signaling, lactate-induced acidosis, and HIF-1α-mediated pseudo-hypoxia, which together impair anti-tumor immunity and facilitate disease persistence. Importantly, these immunometabolic dependencies provide actionable therapeutic vulnerabilities. Targeted strategies, including IDH1/2 inhibitors (ivosidenib and enasidenib), BCL-2 inhibition (venetoclax), niche-disrupting agents (plerixafor and uproleselan), OXPHOS inhibitors (IACS-010759 and metformin), and immunometabolic interventions such as IDO1 inhibitors and CAR-T therapies represent emerging precision approaches. Collectively, this integrative framework highlights the BM microenvironment as a central regulator of cancer cell metabolism and immune evasion, underscoring the potential of immunometabolic targeting to overcome therapeutic resistance and enable next-generation precision medicine in hematologic diseases.