Megakaryocyte–Platelet Immunometabolism in Leukemic Niche Remodeling

Megakaryocytes (MKs) and platelets are increasingly recognized as active regulators of the bone marrow (BM) microenvironment rather than passive effectors of thrombopoiesis and hemostasis. Recent single-cell and lineage-tracing studies have established that megakaryopoiesis generates functionally heterogeneous populations, including immune-biased and niche-supporting subsets that shape hematopoietic stem cell (HSC) behavior, inflammatory tone, and vascular homeostasis. In leukemia, these regulatory circuits are systematically rewired to establish a marrow niche that suppresses normal hematopoiesis while sustaining leukemic stem cell (LSC) fitness through cytokine gradients, stromal remodeling, and direct cell-to-cell communication. In this focused review, we propose that the immune MK (iMK)–platelet axis is a central driver of leukemic niche remodeling. We discuss how iMK states arise under leukemic pressure, how MK heterogeneity encodes distinct niche instructions, and how platelet-derived extracellular vesicles (EVs) distribute inflammatory signals across the marrow and systemic circulation. Within this framework, we position mitochondrial stress outputs—such as reactive oxygen species (mtROS), mitochondrial DNA (mtDNA) release, metabolic rewiring, and mitochondria-containing EV secretion—not as isolated phenomena, but as mechanistic amplifiers embedded within the broader inflammatory and niche-regulatory programs of MKs and platelets. We further highlight preleukemic inflammatory states as an underappreciated entry point for therapeutic intervention, and propose three clinically actionable axes: inflammatory niche interruption, mitochondrial stress modulation, and platelet–leukemia communication blockade. This framework aligns with emerging concepts in MK heterogeneity, innate immune sensing, endothelial remodeling, and preleukemic signaling, and positions the MK–platelet axis as a promising therapeutic framework in leukemia-associated niche remodeling.