Cancer alters the function of multiple organs beyond those targeted by metastasis^1,2. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs—particularly palmitic acid—induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.

癌症改变的多个器官的功能超出了转移目标^1,2 。在这里，我们发现炎症、脂肪肝和代谢失调是小鼠模型和肝外转移患者肝脏受到系统性影响的标志。我们发现肿瘤源性细胞外囊泡和颗粒 (EVP) 是癌症诱导的肝脏重编程的关键介质，可以通过消除Rab27a来减少肿瘤 EVP 的分泌来逆转这种重编程。所有 EVP 亚群、外泌体，主要是外泌体，都可能导致肝功能失调。肿瘤EVP中的脂肪酸——尤其是棕榈酸——诱导库普弗细胞分泌肿瘤坏死因子（TNF），产生促炎微环境，抑制脂肪酸代谢和氧化磷酸化，并促进脂肪肝形成。值得注意的是，库普弗细胞消融或 TNF 阻断显着减少了肿瘤诱导的脂肪肝的产生。肿瘤植入或肿瘤 EVP 预处理会减少细胞色素 P450 基因表达，并以 TNF 依赖性方式减弱药物代谢。我们还在后来发生肝外转移的胰腺癌​​患者的无肿瘤肝脏中观察到诊断时脂肪肝和细胞色素 P450 表达降低，这凸显了我们研究结果的临床相关性。值得注意的是，肿瘤 EVP 教育增强了化疗的副作用，包括骨髓抑制和心脏毒性，这表明肿瘤来源的 EVP 对肝脏的代谢重编程可能会限制癌症患者的化疗耐受性。 我们的结果揭示了肿瘤源性 EVP 如何失调肝功能及其与 TNF 抑制一起的靶向潜力，以预防脂肪肝形成和增强化疗疗效。