Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease for which better therapies are urgently needed. Fibroblasts and macrophages are heterogeneous cell populations able to enhance metastasis, but the role of a macrophage-fibroblast crosstalk in regulating their pro-metastatic functions remains poorly understood. Here we deconvolve how macrophages regulate metastasis-associated fibroblast (MAF) heterogeneity in the liver. We identify three functionally distinct MAF populations, among which the generation of pro-metastatic and immunoregulatory myofibroblastic-MAFs (myMAFs) critically depends on macrophages. Mechanistically, myMAFs are induced through a STAT3-dependent mechanism driven by macrophage-derived progranulin and cancer cell-secreted leukaemia inhibitory factor (LIF). In a reciprocal manner, myMAF secreted osteopontin promotes an immunosuppressive macrophage phenotype resulting in the inhibition of cytotoxic T cell functions. Pharmacological blockade of STAT3 or myMAF-specific genetic depletion of STAT3 restores an anti-tumour immune response and reduces metastases. Our findings provide molecular insights into the complex macrophage–fibroblast interactions in tumours and reveal potential targets to inhibit PDAC liver metastasis.

胰腺导管腺癌（PDAC）是一种高度转移性疾病，迫切需要更好的治疗方法。成纤维细胞和巨噬细胞是能够增强转移的异质细胞群，但巨噬细胞-成纤维细胞串扰在调节其促转移功能中的作用仍知之甚少。在这里，我们对巨噬细胞如何调节肝脏中转移相关成纤维细胞（MAF）异质性进行了解构。我们确定了三个功能不同的 MAF 群体，其中促转移和免疫调节肌成纤维细胞 MAF (myMAF) 的生成主要依赖于巨噬细胞。从机制上讲，myMAF 是通过巨噬细胞衍生的颗粒体蛋白前体和癌细胞分泌的白血病抑制因子 (LIF) 驱动的 STAT3 依赖性机制诱导的。 myMAF 分泌的骨桥蛋白以相反的方式促进免疫抑制巨噬细胞表型，从而抑制细胞毒性 T 细胞功能。 STAT3 的药理学阻断或 STAT3 的 myMAF 特异性基因耗竭可恢复抗肿瘤免疫反应并减少转移。我们的研究结果为肿瘤中复杂的巨噬细胞-成纤维细胞相互作用提供了分子见解，并揭示了抑制 PDAC 肝转移的潜在靶点。