Inflammation as a central driver in AML pathogenesis and therapy resistance.

Inflammation is a prominent feature of the bone marrow microenvironment in acute myeloid leukemia and contributes to leukemic evolution, progression, and therapeutic resistance. Accumulating evidence indicates that inflammatory signals in AML arise from multiple sources, including age-associated inflammaging, mutation-driven pathways, cell-intrinsic stress programs, and external inflammatory stimuli such as infections. These signals collectively facilitate the progression from clonal hematopoiesis and other pre-leukemic states to overt leukemia and support malignant expansion. Leukemic blasts, immune effector and regulatory cells, mesenchymal stromal cells, and endothelial cells collectively establish an inflammatory niche through the production of cytokines and chemokines. This niche supports leukemic stem cell maintenance and fitness, promotes metabolic adaptation and survival, and disrupts normal hematopoiesis and immune surveillance. The inflammatory microenvironment can also compromise therapeutic efficacy by inducing drug tolerance, reinforcing protective bone marrow niches, and reshaping responses to chemotherapy, targeted therapies, immunotherapies, and transplantation-associated graft-versus-leukemia effects. Although increasing mechanistic insights have inspired strategies aimed at neutralizing inflammatory mediators, blocking downstream signaling pathways, or reprogramming the microenvironment to restore anti-leukemic immunity, such anti-inflammatory approaches remain incompletely explored in clinical practice. A deeper understanding of cell type-specific inflammatory circuits and cytokine interactions will be essential for developing rational combination therapies to overcome microenvironment-driven resistance.