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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\u2010selectin. Adipocytes further support tumor bioenergetics by supplying free fatty acids (FFAs) that fuel fatty acid oxidation (FAO), whereas M2\u2010polarized macrophages reinforce immunosuppressive and metabolic adaptations through arginase\u20101 activity and FAO\u2010dependent 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\u2010carbon metabolism, collectively sustaining malignant progression. Concurrently, the BM niche establishes a profoundly immunosuppressive milieu mediated by myeloid\u2010derived suppressor cells (MDSCs), regulatory T cells (Tregs), indoleamine 2,3\u2010dioxygenase 1 (IDO1)\u2010driven kynurenine signaling, lactate\u2010induced acidosis, and HIF\u20101\u03b1\u2010mediated pseudo\u2010hypoxia, which together impair anti\u2010tumor immunity and facilitate disease persistence. Importantly, these immunometabolic dependencies provide actionable therapeutic vulnerabilities. Targeted strategies, including IDH1\/2 inhibitors (ivosidenib and enasidenib), BCL\u20102 inhibition (venetoclax), niche\u2010disrupting agents (plerixafor and uproleselan), OXPHOS inhibitors (IACS\u2010010759 and metformin), and immunometabolic interventions such as IDO1 inhibitors and CAR\u2010T 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\u2010generation precision medicine in hematologic diseases.<\/jats:p>","DOI":"10.1002\/cbin.70217","type":"journal-article","created":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T10:10:31Z","timestamp":1791022231000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunometabolic Reprogramming in the Bone Marrow Niche: Mechanisms, Plasticity, and Precision Therapeutic Targeting"],"prefix":"10.1002","volume":"50","author":[{"given":"Adrian","family":"Khu","sequence":"first","affiliation":[{"name":"Faculty of Medicine Universitas Methodist Indonesia  Sumatera Utara Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander 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