Integrative transcriptomics defines CD36 as a key regulator of immunometabolic signaling in acute myeloid leukemia

Acute myeloid leukemia (AML) is characterized by extensive immunometabolic rewiring that drives leukemic progression and fosters immune evasion.

This study investigates regulatory role of CD36 as an immunometabolic mediator in AML pathogenesis.

Integrated bulk transcriptomics, single-cell RNA sequencing, and in-vitro validation were performed. Macrophage co-localization was validated using colorectal cancer (CRC) spatial transcriptomics.

CD36 was identified as a central hub in preserved immunometabolic modules, enriched for TLR signaling, lipid metabolism, antigen-presenting pathways, and cytokine-cytokine receptor interactions. Drug sensitivity analysis revealed that high CD36 expression showed greater sensitivity to venetoclax and GSK626616AC. CD36 drives AML immune cycle and revealed a strong association with AML functional states, including inflammation, differentiation, apoptosis, invasion, quiescence, and hypoxia. Single-cell analysis indicated CD36 upregulation in monocyte and macrophage clusters, facilitating ligand-receptor communication with T cells, which emphasizes CD36's role in shaping immune microenvironment. Spatial transcriptomics analysis of colorectal cancer confirmed a significant CD36-CD68 colocalization in macrophages. CD36 also influenced monocyte to macrophage differentiation in AML cells. CD36 deficiency significantly reduces AML cells' proliferation and leads to G0/G1 phase expansion, accompanied by E2F4/E2F5/RB1 modulation. Hallmark enrichment analysis unveiled that CD36-high expression leukemic cells, CD36 immune signatures, and monocytes/macrophages showed enrichment in key immune and inflammatory pathways, including TNFα/NF-κB, IL6/JAK/STAT3, and IL2/STAT5 signaling, mTORC1 activation, interferon alpha and gamma responses, and reactive oxygen species pathways.

Integration of transcriptomics and spatial validation revealed robust CD36-mediated immunometabolic signaling in AML, which further requires comprehensive in-vitro and in-vivo validation.