Efferocytosis reprograms the tumor microenvironment to promote pancreatic cancer liver metastasis. Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic cancer with a poor prognosis, and liver metastasis is a major cause of mortality. This study reveals that efferocytosis, the engulfment of apoptotic cells by macrophages, plays a critical role in promoting PDAC liver metastasis. The process involves the clearance of dead cells by macrophages, which leads to macrophage reprogramming and the promotion of an immunosuppressive tumor microenvironment. Mechanistically, progranulin expression in macrophages is essential for efficient efferocytosis, as it controls lysosomal acidification and the degradation of lysosomal cargo, leading to LXRα/RXRα-mediated macrophage conversion and upregulation of arginase 1. Pharmacological inhibition of efferocytosis or genetic depletion of progranulin in macrophages impairs macrophage conversion, enhances CD8+ T cell function, and reduces liver metastasis. These findings highlight the role of macrophage functions in tissue repair in promoting liver metastasis and identify potential therapeutic targets for preventing PDAC liver metastasis. The study also shows that progranulin regulates lysosomal acidification via the cystic fibrosis transmembrane conductance regulator (CFTR), and pharmacological inhibition of CFTR impairs efferocytosis-induced macrophage polarization and PDAC liver metastasis. Overall, the study provides new insights into the mechanisms underlying PDAC liver metastasis and highlights the importance of targeting efferocytosis and macrophage function in the treatment of this aggressive cancer.Efferocytosis reprograms the tumor microenvironment to promote pancreatic cancer liver metastasis. Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic cancer with a poor prognosis, and liver metastasis is a major cause of mortality. This study reveals that efferocytosis, the engulfment of apoptotic cells by macrophages, plays a critical role in promoting PDAC liver metastasis. The process involves the clearance of dead cells by macrophages, which leads to macrophage reprogramming and the promotion of an immunosuppressive tumor microenvironment. Mechanistically, progranulin expression in macrophages is essential for efficient efferocytosis, as it controls lysosomal acidification and the degradation of lysosomal cargo, leading to LXRα/RXRα-mediated macrophage conversion and upregulation of arginase 1. Pharmacological inhibition of efferocytosis or genetic depletion of progranulin in macrophages impairs macrophage conversion, enhances CD8+ T cell function, and reduces liver metastasis. These findings highlight the role of macrophage functions in tissue repair in promoting liver metastasis and identify potential therapeutic targets for preventing PDAC liver metastasis. The study also shows that progranulin regulates lysosomal acidification via the cystic fibrosis transmembrane conductance regulator (CFTR), and pharmacological inhibition of CFTR impairs efferocytosis-induced macrophage polarization and PDAC liver metastasis. Overall, the study provides new insights into the mechanisms underlying PDAC liver metastasis and highlights the importance of targeting efferocytosis and macrophage function in the treatment of this aggressive cancer.