Abstract: Hepatocellular carcinoma (HCC), a common form of primary liver cancer and a leading cause of cancer-related mortality, remains challenging to treat due to therapeutic resistance and the low response rate to immune checkpoint inhibitors (ICIs). The gut microbiota modulates the hepatic immune microenvironment through the gut-liver axis and plays a pivotal role in the initiation, progression, and immunotherapy of HCC. This review systematically and comprehensively examines how the gut microbiota reshapes the HCC immune microenvironment by influencing macrophage polarization, dendritic cell antigen presentation, natural killer (NK) cell cytotoxicity, and T-cell function through microbial metabolites and immune signaling pathways, as well as its role in reshaping the immune microenvironment of HCC. The composition of the HCC immune microenvironment is closely associated with the therapeutic efficacy of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors. Specifically, specific microbial taxa may serve as predictive biomarkers of treatment response. In addition, interventions targeting the microbiota, such as probiotics, faecal microbiota transplantation and prebiotics, have shown potential to improve the effectiveness of ICIs in animal models and early clinical studies by enhancing antitumor immune responses through modulation of the microbial community structure. Therefore, the gut microbiota may offer novel therapeutic targets and strategies for HCC immunotherapy, although further clinical studies are required to validate their clinical applicability and optimize patient outcomes. This review may serve as a reference for the development and application of gut microbiota-related therapeutic targets and strategies in HCC immunotherapy. It may also inform future clinical studies integrating microbiota interventions to improve treatment outcomes in patients with HCC.

Key words: Hepatocellular carcinoma, Gut microbiota, Immune microenvironment, Immune checkpoint inhibitors, Strategies of microbiota intervention

摘要： 肝细胞癌（HCC）作为常见原发性肝癌及癌症相关死亡主要原因，其治疗受限于耐药性及免疫检查点抑制剂（ICIs）低响应率。肠道菌群通过肠 - 肝轴调控肝脏免疫微环境，在HCC发生发展及免疫治疗中起关键作用。本文系统、全面地探讨了肠道菌群通过代谢产物及免疫信号影响巨噬细胞极化、树突状细胞抗原提呈、自然杀伤（NK）细胞毒性及 T 细胞功能，及其对HCC免疫微环境的重塑；HCC免疫微环境的组成与程序性死亡受体1（PD-1）/程序性死亡配体-1（PD-L1）、细胞毒性T细胞相关蛋白4（CTLA-4）抑制剂疗效密切相关，特征菌群可作为疗效预测生物标志物。此外，益生菌、粪便微生物群移植及益生元等菌群干预策略，通过调节菌群结构改善抗肿瘤免疫应答，在动物模型及初步临床研究中显示出增强 ICIs 疗效的潜力。因此，肠道菌群可为HCC免疫治疗提供新靶点与策略，未来需通过临床研究验证其临床适用性，以优化患者预后。本文为HCC免疫治疗中肠道菌群相关新靶点与策略的开发及应用提供参考，并为开展HCC免疫治疗结合菌群干预的临床研究及患者预后的优化提供借鉴。

关键词: 肝细胞癌, 肠道菌群, 免疫微环境, 免疫检查点抑制剂, 菌群干预策略