Abstract B078: APMAP functions as a tumor-intrinsic target sensitizing cancer cells to macrophage-mediated phagocytosis

Abstract Macrophage-mediated phagocytosis plays a critical role in cancer cell elimination. Here, we developed an in vitro tumor-macrophage co-culture platform for unbiased identification of factors that impede macrophage phagocytosis using genome-wide CRISPR knockout. From the functional genomics screen, we identified APMAP as a tumor-intrinsic phagocytosis sensitizer. In vitro experiments validated that APMAP depletion in tumor cells enhances direct engulfment and selective killing of tumor cells by macrophages. In vivo experiments showed that APMAP depletion attenuates tumor growth and displays combinational effects with cetuximab in an MDA-MB-468 orthotopic model. To dissect the mechanism of action, we conducted a whole genome anchor screen using an APMAP-WT/KO isogenic pair and identified fatty acid biosynthesis pathway genes (including FASN, ACLY and ACC) that are required for APMAP deficiency-induced phenotypes; the metabolomics analysis suggests that sphingolipids are potential APMAP substrates. To inform drug discovery, we demonstrated that enzymatic activity is required for APMAP-enhanced phagocytosis. We further demonstrated that as a transmembrane protein, intracellularly localized APMAP was functional as a phagocytosis sensitizer, thereby suggesting that a small molecule inhibitor is preferred over a blocking antibody as a therapeutic strategy for disrupting APMAP activity. Citation Format: Rachel Davidson, Ye Wang, Lei Ji, Grace Trombley, Wenrong Zhou, Binzhang Shen, Ashley Choi, Hannah Stowe, Shangtao Liu, Samuel R. Meier, Brian Doyon, Douglas A. Whittington, Yi Yu, Teng Teng, Jannik N. Andersen, Alan Huang, Chengyin Min, Salam Shaaban, Serge Gueroussov. APMAP functions as a tumor-intrinsic target sensitizing cancer cells to macrophage-mediated phagocytosis [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B078.