These findings elucidate a novel MFAP2-ITGB8-FAK-ERK1/2-ETS2-CYP27A1-LXRβ signaling axis, significantly activated by CAFs-derived MFAP2 in both in vitro and in vivo models, contributing to immune exhaustion and tumor progression. This evidence concerns the gene CYP27A1 and neoplasm.