Fatty acid transport protein 2 reprograms neutrophils in cancer.

Polymorphonuclear myeloid-derived suppressor cells are pathologically activated neutrophils that are crucial for the regulation of immune responses in cancer. These cells contribute to the failure of cancer therapies and are associated with poor clinical outcomes. Despite recent advances in the understanding of biology, the mechanisms responsible for the pathological activation of neutrophils are not well defined, and this limits the selective targeting of these cells. Here we report that mouse and human exclusively upregulate fatty acid transport protein 2 (FATP2). Overexpression of FATP2 in duanyu1451-MDSCs was controlled by granulocyte-macrophage colony-stimulating factor, through the activation of the transcription factor. Deletion of FATP2 abrogated the suppressive activity of The main mechanism of FATP2-mediated suppressive activity involved the uptake of arachidonic acid and the synthesis of prostaglandin E₂. The selective pharmacological inhibition of FATP2 abrogated the activity of duanyu1451-MDSCs and substantially delayed tumour progression. In combination with checkpoint inhibitors, FATP2 inhibition blocked tumour progression in mice. Thus, FATP2 mediates the acquisition of immunosuppressive activity by duanyu1451-MDSCs and represents a target to inhibit the functions of duanyu1451-MDSCs selectively and to improve the efficiency of cancer therapy.

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