SLC38A4 promotes Kupffer cell phagocytosis and suppresses tumor liver metastasis

Metastasis is the main cause of cancer-related death. The liver is an organ with high metastatic tropism for various malignancies. Hepatic-resident macrophage Kupffer cells are the major non-parenchymal cells in the liver that phagocytize disseminated tumor cells to restrict liver metastasis. However, the critical molecules that modulate phagocytosis of tumor cells by Kupffer cells are still largely unknown. Here, we identified SLC38A4 expressed on tumor cells as a critical suppressor during tumor liver metastasis. SLC38A4 enhances the phagocytosis of various tumor cells by Kupffer cells, leading to a reduction in liver metastasis. Mechanistically, SLC38A4 downregulates the expression of "don't eat me" molecule CD24, which mediates the roles of SLC38A4 in Kupffer cells phagocytosis and tumor liver metastasis. MYC directly binds to CD24 promoter and activates CD24 transcription. Through downregulating MYC, SLC38A4 suppresses the expression of CD24. Patients with low SLC38A4 expression in tumors have more liver metastases. This study demonstrates that SLC38A4 promotes Kupffer cell phagocytosis and restricts tumor liver metastasis by suppressing CD24. The SLC38A4/MYC/CD24 axis represents a novel phagocytosis checkpoint for Kupffer cells and a potential therapeutic target for liver metastasis.