Cholesterol Reprogramming in Acute Myeloid Leukemia: Integrating Tumor-Intrinsic Metabolism and Immune Crosstalk

Acute myeloid leukemia (AML) is a genetically and biologically heterogeneous hematologic neoplasm that arises from the clonal transformation of hematopoietic progenitor cells. AML cells undergo extensive metabolic reprogramming to sustain proliferation, survival, and adaptation to therapeutic stress. Among these alterations, cholesterol metabolism has emerged as a critical determinant of leukemic cell fitness. AML cells enhance cholesterol biosynthesis, uptake, trafficking, and storage, generating a dynamic network that supports membrane organization, mitochondrial function, oncogenic signaling, and resistance to therapy. Beyond these tumor-intrinsic roles, accumulating evidence indicates that cholesterol and its metabolites actively shape communication between leukemic and immune cells, influencing immune checkpoint expression, inflammatory signaling, and antitumor immune responses within the bone marrow microenvironment. This narrative review examines the mechanisms underlying cholesterol reprogramming in AML and discusses how alterations in cholesterol homeostasis integrate metabolic adaptation with immune regulation. Particular emphasis is placed on the interplay between cholesterol metabolism, leukemic stem cell persistence, therapeutic resistance, and immune dysfunction. Emerging therapeutic strategies targeting cholesterol-related pathways are also considered. Collectively, these findings position cholesterol metabolism as a central interface between tumor-intrinsic biology and immune crosstalk, highlighting its potential as a therapeutic vulnerability in AML.