Monoclonal antibody therapies targeting tumour antigens drive cancer cell elimination in large part by triggering macrophage phagocytosis of cancer cells^{1,2,3,4,5,6,7}. However, cancer cells evade phagocytosis using mechanisms that are incompletely understood. Here we develop a platform for unbiased identification of factors that impede antibody-dependent cellular phagocytosis (ADCP) using complementary genome-wide CRISPR knockout and overexpression screens in both cancer cells and macrophages. In cancer cells, beyond known factors such as CD47, we identify many regulators of susceptibility to ADCP, including the poorly characterized enzyme adipocyte plasma membrane-associated protein (APMAP). We find that loss of APMAP synergizes with tumour antigen-targeting monoclonal antibodies and/or CD47-blocking monoclonal antibodies to drive markedly increased phagocytosis across a wide range of cancer cell types, including those that are otherwise resistant to ADCP. Additionally, we show that APMAP loss synergizes with several different tumour-targeting monoclonal antibodies to inhibit tumour growth in mice. Using genome-wide counterscreens in macrophages, we find that the G-protein-coupled receptor GPR84 mediates enhanced phagocytosis of APMAP-deficient cancer cells. This work reveals a cancer-intrinsic regulator of susceptibility to antibody-driven phagocytosis and, more broadly, expands our knowledge of the mechanisms governing cancer resistance to macrophage phagocytosis.

靶向肿瘤抗原的单克隆抗体疗法在很大程度上通过触发癌细胞的巨噬细胞吞噬作用来驱动癌细胞消除^{1,2,3,4,5,6,7}. 然而，癌细胞使用不完全了解的机制逃避吞噬作用。在这里，我们开发了一个平台，用于在癌细胞和巨噬细胞中使用互补的全基因组 CRISPR 敲除和过表达筛选来无偏见地识别阻碍抗体依赖性细胞吞噬作用 (ADCP) 的因素。在癌细胞中，除了 CD47 等已知因素外，我们还发现了许多对 ADCP 易感性的调节因子，包括未被充分表征的酶脂肪细胞质膜相关蛋白 (APMAP)。我们发现，APMAP 的缺失与肿瘤抗原靶向单克隆抗体和/或 CD47 阻断单克隆抗体协同作用，可显着增加多种癌细胞类型的吞噬作用，包括那些对 ADCP 具有抗性的细胞。此外，我们表明 APMAP 损失与几种不同的肿瘤靶向单克隆抗体协同作用以抑制小鼠肿瘤生长。在巨噬细胞中使用全基因组反筛选，我们发现 G 蛋白偶联受体 GPR84 介导 APMAP 缺陷癌细胞的增强吞噬作用。这项工作揭示了对抗体驱动的吞噬作用易感性的癌症内在调节因子，更广泛地说，扩展了我们对控制癌症对巨噬细胞吞噬作用的抵抗力的机制的认识。