肝细胞癌（HCC）是原发性肝癌的主要类型，因其对全身治疗的抵抗而臭名昭著。该领域在过去十年中取得了巨大飞跃，FDA 批准的晚期 HCC 疗法数量从 1 种增加到 9 种。尽管酪氨酸激酶抑制剂仍然是单药治疗最常见的一线选择，但免疫疗法的临床成功检查点抑制剂，特别是在 HCC 中与抗 VEGF/VEGFR 联合使用时，可能会改变治疗格局。虽然免疫检查点抑制剂为 HCC 带来了令人兴奋的治疗收入，但最近的研究表明，主要由代谢功能障碍相关脂肪性肝炎 (MASH) 引起的非病毒性 HCC 对免疫检查点抑制剂具有明显且不太有利的反应。 MASH 是 HCC 增长最快的病因。 MASH-HCC 的免疫微环境受到脂肪变性诱导的脂肪性肝炎和肝损伤之间反复循环的相互交织的病理过程的影响。在这里，我们及时总结了 MASH-HCC 的免疫微环境。我们将深入研究利用单细胞 RNA 测序、空间转录组学和质谱流式成像等尖端技术来解决 MASH-HCC 免疫生态系统的复杂性。我们还将讨论临床前模型中 MASH-HCC 的治疗创新，例如代谢抑制剂、表观遗传抑制剂和免疫调节剂。这些抑制剂都具有颠覆MASH-HCC免疫微环境的能力，提高抗PD-1的效率。在等待新药在临床试验中进行测试时，从这些研究中获得的知识对于制定个性化且有效的 MASH-HCC 治疗策略至关重要。版权所有 © 2024 作者。由 Wolters Kluwer Health, Inc. 代表美国肝病研究协会出版。

Hepatocellular carcinoma (HCC), the major type of primary liver cancer, is notorious for its resistance to systemic treatments. The field has made a great leap in the past decade, with the number of FDA-approved therapies for advanced HCC increasing from 1 to 9. Although tyrosine kinase inhibitors remain the most common first-line option as monotherapy treatment, the clinical success of immune checkpoint inhibitors, especially when used in combination with anti-VEGF/VEGFR in HCC will likely transform the treatment landscape. While immune checkpoint inhibitors represent an exciting therapeutic revenue for HCC, recent studies have revealed that nonviral HCC, which is primarily caused by metabolic dysfunction-associated steatotic hepatitis (MASH), has a distinct and less favorable response to the immune checkpoint inhibitors. MASH is the most rapidly increasing etiology for HCC. The immune microenvironment of MASH-HCC is greatly affected by the intertwined pathological processes of steatosis-induced iterative cycles between steatohepatitis and liver injury. Here, we present a timely summary of the immune microenvironment of MASH-HCC. We will delve into the use of cutting-edge technologies, such as single-cell RNA sequencing, spatial transcriptomics, and mass cytometry imaging, to deconvolute the complexity of the immune ecosystem in MASH-HCC. We will also discuss the novel therapeutic innovations for MASH-HCC in preclinical models, such as the metabolic inhibitor, epigenetic inhibitor, and immunomodulator. These inhibitors all have the ability to subvert the immune microenvironment of MASH-HCC, improving the efficiency of anti-PD-1. While awaiting new drugs to be tested in clinical trials, the knowledge gained from these investigations is crucial for the development of personalized and effective treatment strategies for MASH-HCC.Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.