Pancreatic ductal adenocarcinoma is a highly metastatic disease and macrophages support liver metastases. Efferocytosis, or engulfment of apoptotic cells by macrophages, is an essential process in tissue homeostasis and wound healing, but its role in metastasis is less well understood. Here, we found that the colonization of the hepatic metastatic site is accompanied by low-grade tissue injury and that efferocytosis-mediated clearance of parenchymal dead cells promotes macrophage reprogramming and liver metastasis. Mechanistically, progranulin expression in macrophages is necessary for efficient efferocytosis by controlling lysosomal acidification via cystic fibrosis transmembrane conductance regulator and the degradation of lysosomal cargo, resulting in LXRα/RXRα-mediated macrophage conversion and upregulation of arginase 1. Pharmacological blockade of efferocytosis or macrophage-specific genetic depletion of progranulin impairs macrophage conversion, improves CD8⁺ T cell functions, and reduces liver metastasis. Our findings reveal how hard-wired functions of macrophages in tissue repair contribute to liver metastasis and identify potential targets for prevention of pancreatic ductal adenocarcinoma liver metastasis.

胰腺导管腺癌是一种高度转移性疾病，巨噬细胞支持肝转移。胞吞作用或巨噬细胞吞噬凋亡细胞是组织稳态和伤口愈合的重要过程，但其在转移中的作用尚不清楚。在这里，我们发现肝转移部位的定植伴随着低度组织损伤，胞吞作用介导的实质死亡细胞的清除促进巨噬细胞重编程和肝转移。从机制上讲，巨噬细胞中颗粒体蛋白前体的表达对于有效的胞吞作用是必要的，通过囊性纤维化跨膜电导调节剂控制溶酶体酸化和溶酶体货物的降解，导致 LXRα/RXRα 介导的巨噬细胞转化和精氨酸酶的上调 1。 胞吞作用或巨噬细胞的药理学阻断 -颗粒体蛋白前体的特异性基因缺失会损害巨噬细胞转化，改善 CD8 ⁺ T 细胞功能，并减少肝转移。我们的研究结果揭示了巨噬细胞在组织修复中的硬连线功能如何促进肝转移，并确定了预防胰腺导管腺癌肝转移的潜在靶标。