CD36-mediated metabolic crosstalk between tumor cells and macrophages affects liver metastasis

Ping Yang, Hong Qin, Yiyu Li, Anhua Xiao, Enze Zheng, Han Zeng, Chunxiao Su, Xiaoqing Luo, Qiannan Lu, Meng Liao, Lei Zhao, Li Wei, Zac Varghese, John F. Moorhead, Yaxi Chen () and Xiong Z. Ruan ()
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Ping Yang: Chongqing Medical University
Hong Qin: Chongqing Medical University
Yiyu Li: Chongqing Medical University
Anhua Xiao: Chongqing Medical University
Enze Zheng: Chongqing Medical University
Han Zeng: Chongqing Medical University
Chunxiao Su: Chongqing Medical University
Xiaoqing Luo: Chongqing Medical University
Qiannan Lu: Chongqing Medical University
Meng Liao: Chongqing Medical University
Lei Zhao: Chongqing Medical University
Li Wei: Chongqing Medical University
Zac Varghese: University College London Medical School, Royal Free Campus, University College London
John F. Moorhead: University College London Medical School, Royal Free Campus, University College London
Yaxi Chen: Chongqing Medical University
Xiong Z. Ruan: Chongqing Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Liver metastasis is highly aggressive and treatment-refractory, partly due to macrophage-mediated immune suppression. Understanding the mechanisms leading to functional reprogramming of macrophages in the tumor microenvironment (TME) will benefit cancer immunotherapy. Herein, we find that the scavenger receptor CD36 is upregulated in metastasis-associated macrophages (MAMs) and deletion of CD36 in MAMs attenuates liver metastasis in mice. MAMs contain more lipid droplets and have the unique capability in engulfing tumor cell-derived long-chain fatty acids, which are carried by extracellular vesicles. The lipid-enriched vesicles are preferentially partitioned into macrophages via CD36, that fuel macrophages and trigger their tumor-promoting activities. In patients with liver metastases, high expression of CD36 correlates with protumoral M2-type MAMs infiltration, creating a highly immunosuppressive TME. Collectively, our findings uncover a mechanism by which tumor cells metabolically interact with macrophages in TME, and suggest a therapeutic potential of targeting CD36 as immunotherapy for liver metastasis.

Date: 2022
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DOI: 10.1038/s41467-022-33349-y

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