![]() ![]() The functional reprogramming of macrophages is a complex process which is not necessarily dependent on IL-4 and has not yet been elucidated. Macrophages, the most abundant myeloid cells infiltrating the tumor microenvironment (TME), are endowed with a protumoral M2-like phenotype, facilitating tumor initiation, progression and metastasis 4. ![]() Targeting macrophages may improve cancer immunotherapy for treating liver metastasis 3. The massive accumulation of macrophages in liver metastasis greatly contributes to reduced response to immunotherapy and poor outcome. Nevertheless, clinical benefits from immunotherapy are observed in only 15–20% of patients with liver metastases 1, 2. Cancer immunotherapy harnessing the immune system to battle tumors has achieved unprecedented success in the treatment of multiple malignancies. Patients with liver metastases are strongly associated with poor prognosis and diminished therapeutic responsiveness. Metastasis is the leading cause of cancer-related death, and the liver is the most common site of cancer metastases. 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. In patients with liver metastases, high expression of CD36 correlates with protumoral M2-type MAMs infiltration, creating a highly immunosuppressive TME. The lipid-enriched vesicles are preferentially partitioned into macrophages via CD36, that fuel macrophages and trigger their tumor-promoting activities. 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. 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. Understanding the mechanisms leading to functional reprogramming of macrophages in the tumor microenvironment (TME) will benefit cancer immunotherapy. Liver metastasis is highly aggressive and treatment-refractory, partly due to macrophage-mediated immune suppression. ![]()
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