SMAGP suppresses cancer cell phagocytosis by engaging the macrophage inhibitory receptor PILRalpha

Monoclonal antibody therapies can eliminate cancer cells in part by promoting antibody-dependent cellular phagocytosis (ADCP) by macrophages. However, many cancer cells evade ADCP through poorly understood anti-phagocytic mechanisms, limiting the effectiveness of antibody-based treatments. To identify such factors in anti-CD47 non-responsive RKO colon cancer cells, we conduct an anti-phagocytic gene-focused CRISPR knockout screen and discover the metastasis-linked gene SMAGP as a potent suppressor of phagocytosis. Using CRISPR-based screens in macrophages, we further uncover the inhibitory receptor PILRalpha as essential for SMAGP-mediated suppression of phagocytosis. Deletion of PILRalpha in macrophages or treatment with anti-PILRalpha antibodies abolishes SMAGP's protective effect. Mutational analysis shows that predicted PILRalpha-binding motifs on SMAGP are required for its ability to block phagocytosis. This work reveals a novel SMAGP-PILRalpha signaling axis that enables cancer cells to resist ADCP and suggests new therapeutic strategies to sensitize tumors to antibody-driven macrophage clearance.