Importantly, we found that α5β1 integrin, but not PIR‐B, is expressed on tumor cells and essential for ANGPTL2‐mediated epigenetic MHC‐I repression in tumor cells, suggesting that ANGPTL2 derived from tumor stroma or tumor cells acts through distinct receptors, namely PIR‐B or α5β1 integrin, respectively, to promote signaling with opposing effects on anti‐tumor immunity. Here, ANGPTL2 is linked to neoplasm.