为头颈鳞状细胞癌（HNSCC）患者开发有效的治疗方法是一项重大挑战。西妥昔单抗是 HNSCC 的一线靶向治疗药物，但疗效有限。在这里，我们使用混合 CRISPR 筛选来寻找可以与西妥昔单抗协同作用的靶点，并确定 CD47 为主要候选者。 CD47 抑制不是抑制癌细胞增殖，而是促进西妥昔单抗触发的抗体依赖性细胞吞噬作用 (ADCP)，从而增强巨噬细胞介导的癌细胞清除。 CD47-SIRPα阻断剂与西妥昔单抗的组合在体内表现出强大的抗癌活性。除了阻断吞噬检查点外，CD47-SIRPα抑制还可上调巨噬细胞表面的CD11b/CD18，从而加速巨噬细胞与癌细胞之间的细胞间粘附，从而增强随后的吞噬作用。抑制巨噬细胞 CD11b/CD18 与癌细胞 ICAM1 之间的相互作用，消除了 CD47-SIRPα 阻断诱导的细胞间粘附和吞噬作用。因此，CD47-SIRPα阻断通过CD11b/CD18-ICAM1介导的细胞间粘附增强ADCP，并使HNSCC对西妥昔单抗敏感。

Developing effective treatments for patients with head and neck squamous cell carcinoma (HNSCC) is a significant challenge. Cetuximab, a first-line targeted therapy for HNSCC, exhibits limited efficacy. Here, we used pooled CRISPR screening to find targets that can synergize with cetuximab and identified CD47 as the leading candidate. Rather than inhibiting cancer cell proliferation, CD47 inhibition promoted cetuximab-triggered antibody-dependent cellular phagocytosis (ADCP), thereby enhancing macrophage-mediated cancer cell removal. The combination of CD47-SIRPα blockade and cetuximab demonstrated strong anticancer activity in vivo. In addition to blocking the phagocytosis checkpoint, CD47-SIRPα inhibition upregulated CD11b/CD18 on the surface of macrophages, which accelerated intercellular adhesion between macrophages and cancer cells to enhance subsequent phagocytosis. Inhibition of the interaction between macrophage CD11b/CD18 and cancer cell ICAM1 eliminated the intercellular adhesion and phagocytosis induced by CD47-SIRPα blockade. Thus, CD47-SIRPα blockade enhances ADCP through CD11b/CD18-ICAM1-mediated intercellular adhesion and sensitizes HNSCC to cetuximab.