A CD36-dependent non-canonical lipid metabolism program promotes immune escape and resistance to hypomethylating agent therapy in AML

作者：He‐Zhou Guo, Rui-Xue Feng, Yanjie Zhang, Yehua Yu, Wei Lu, Jiajia Liu, Shaoxin Yang, Chong Zhao, Zhao-Li Zhang, Shanhe Yu, Hui Jin, Sixuan Qian, Jianyong Li, Jiang Zhu, Jun Shi · 发表于：Cell Reports Medicine · 年份：2024 · DOI：10.1016/j.xcrm.2024.101592 · 被引用次数：43 · 研究领域：Cancer, Lipids, and Metabolism、Peroxisome Proliferator-Activated Receptors、Immune cells in cancer

Environmental lipids are essential for fueling tumor energetics, but whether these exogenous lipids transported into cancer cells facilitate immune escape remains unclear. Here, we find that CD36, a transporter for exogenous lipids, promotes acute myeloid leukemia (AML) immune evasion. We show that, separately from its established role in lipid oxidation, CD36 on AML cells senses oxidized low-density lipoprotein (OxLDL) to prime the TLR4-LYN-MYD88-nuclear factor κB (NF-κB) pathway, and exogenous palmitate transfer via CD36 further potentiates this innate immune pathway by supporting ZDHHC6-mediated MYD88 palmitoylation. Subsequently, NF-κB drives the expression of immunosuppressive genes that inhibit anti-tumor T cell responses. Notably, high-fat-diet or hypomethylating agent decitabine treatment boosts the immunosuppressive potential of AML cells by hijacking CD36-dependent innate immune signaling, leading to a dampened therapeutic effect. This work is of translational interest because lipid restriction by US Food and Drug Administration (FDA)-approved lipid-lowering statin drugs improves the efficacy of decitabine therapy by weakening leukemic CD36-mediated immunosuppression.