VSIG4 Promotes Tumour‐Associated Macrophage M2 Polarization and Immune Escape in Colorectal Cancer via Fatty Acid Oxidation Pathway

Abstract Background V‐set and immunoglobulin domain containing 4 (VSIG4) is a B7‐family‐related protein almost exclusively expressed on macrophages. The difference in its expression mediates the dynamic transformation of the polarization state of macrophages, but the underlying mechanism is still unclear. We sought to reveal the correlation between VSIG4 and the polarization of tumour‐associated macrophages (TAMs) and the immune escape of tumour cells in colorectal cancer (CRC). Methods THP‐1 monocyte‐derived macrophages expressing different levels of VSIG4 were used for in vitro investigations. In addition, the co‐culture system was used to verify the effect of tumour cells on the expression of VSIG4 in macrophages, and the effect of VSIG4 expression level on tumour cells in turn. Subcutaneous xenograft models evaluated the tumour growth inhibition efficacy of VSIG4 blockade as monotherapy and combined with immune checkpoint inhibitors (ICIs). Results CRC cells secreted lactate to promote VSIG4 expression in macrophages. On the contrary, VSIG4 promoted macrophage M2 polarization and induced malignant progression of tumour cells by promoting M2 macrophage secretion of heparin‐bound epidermal growth factor. In vivo experiments confirmed that knockdown VSIG4 inhibited tumour growth and improved the efficacy of ICIs therapy. Mechanistically, lactate secreted by CRC cells promoted its expression by influencing the epigenetic modification of VSIG4 in macrophages. In addition, VSIG4 enhanced the fatty acid oxidation (FAO) of macrophages and upregulated PPAR‐γ expression by activating the JAK2/STAT3 pathway, which ultimately induced M2 polarization of macrophages. Downregulation of VSIG4 or blocking of FAO reversed the M2 polarization process of macrophages. Conclusions Our findings provide a molecular basis for VSIG4 to influence TAMs polarization by regulating the reprogramming of FAO, suggesting that targeting VSIG4 in macrophages could enhance the ICIs efficacy and represent a new combination therapy strategy for immunotherapy of CRC. Key points Colorectal cancer cells secrete lactate to upregulate VSIG4 in macrophages via the H3K18la‐METTL14‐m6A axis. VSIG4 promotes fatty acid oxidation of macrophages and drives its M2‐type polarization. These VSIG4‐expressing M2 macrophages promote tumour progression and an immunosuppressive microenvironment. Inhibition of VSIG4 expression can synergistically enhance the therapeutic effect of anti‐PD‐1 antibody.