Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer and is highly lethal. () infection is an important risk factor for iCCA. Here we investigated the clinical impact and underlying molecular characteristics of infection-related iCCA. We performed single-cell RNA sequencing, whole-exome sequencing, RNA sequencing, metabolomics and spatial transcriptomics in 251 patients with iCCA from three medical centers. Alterations in metabolism and the immune microenvironment of -related iCCAs were validated through an co-culture system and in a mouse model of iCCA. We revealed that infection was significantly associated with iCCA patients’ overall survival and response to immunotherapy. Fatty acid biosynthesis and the expression of fatty acid synthase (FASN), a key enzyme catalyzing long-chain fatty acid synthesis, were significantly enriched in -related iCCAs. iCCA cell lines treated with excretory/secretory products of displayed elevated FASN and free fatty acids. The metabolic alteration of tumor cells was closely correlated with the enrichment of tumor-associated macrophage (TAM)-like macrophages and the impaired function of T cells, which led to formation of an immunosuppressive microenvironment and tumor progression. Spatial transcriptomics analysis revealed that malignant cells were in closer juxtaposition with TAM-like macrophages in -related iCCAs than non--related iCCAs. Importantly, treatment with a FASN inhibitor significantly reversed the immunosuppressive microenvironment and enhanced anti-PD-1 efficacy in iCCA mouse models treated with excretory/secretory products from . We provide novel insights into metabolic alterations and the immune microenvironment in infection-related iCCAs. We also demonstrate that the combination of a FASN inhibitor with immunotherapy could be a promising strategy for the treatment of related iCCAs. (infected patients with intrahepatic cholangiocarcinoma (iCCA) have a worse prognosis and response to immunotherapy than non--infected patients with iCCA. The underlying molecular characteristics of infection-related iCCAs remain unclear. Herein, we demonstrate that upregulation of FASN (fatty acid synthase) and free fatty acids in related iCCAs leads to formation of an immunosuppressive microenvironment and tumor progression. Thus, administration of FASN inhibitors could significantly reverse the immunosuppressive microenvironment and further enhance the efficacy of anti-PD-1 against -related iCCAs.

中文翻译：

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FASN介导的脂肪酸生物合成重塑华支睾吸虫感染相关肝内胆管癌的免疫环境


肝内胆管癌（iCCA）是第二常见的原发性肝癌，具有高度致死性。 ()感染是iCCA的重要危险因素。在这里，我们研究了感染相关 iCCA 的临床影响和潜在分子特征。我们对来自三个医疗中心的 251 名 iCCA 患者进行了单细胞 RNA 测序、全外显子组测序、RNA 测序、代谢组学和空间转录组学。通过共培养系统和 iCCA 小鼠模型验证了相关 iCCA 代谢和免疫微环境的变化。我们发现感染与 iCCA 患者的总体生存率和对免疫治疗的反应显着相关。脂肪酸生物合成和脂肪酸合酶（FASN）（一种催化长链脂肪酸合成的关键酶）的表达在相关的 iCCA 中显着富集。用显示出升高的 FASN 和游离脂肪酸的排泄/分泌产物处理的 iCCA 细胞系。肿瘤细胞的代谢改变与肿瘤相关巨噬细胞（TAM）样巨噬细胞的富集和T细胞功能受损密切相关，从而导致免疫抑制微环境的形成和肿瘤的进展。空间转录组学分析显示，与非相关 iCCA 相比，相关 iCCA 中恶性细胞与 TAM 样巨噬细胞的排列更为紧密。重要的是，在用来自 的排泄/分泌产品治疗的 iCCA 小鼠模型中，使用 FASN 抑制剂治疗显着逆转了免疫抑制微环境并增强了抗 PD-1 功效。我们对感染相关 iCCA 中的代谢改变和免疫微环境提供了新的见解。 我们还证明，FASN 抑制剂与免疫疗法的组合可能是治疗相关 iCCA 的一种有前途的策略。 （肝内胆管癌（iCCA）感染患者的预后和对免疫治疗的反应比非感染 iCCA 患者更差。感染相关 iCCA 的潜在分子特征仍不清楚。在此，我们证明 FASN（脂肪酸合成酶）的上调）和相关 iCCA 中的游离脂肪酸导致免疫抑制微环境的形成和肿瘤进展，因此，给予 FASN 抑制剂可以显着逆转免疫抑制微环境，并进一步增强抗 PD-1 针对相关 iCCA 的功效。