The advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment paradigm for hepatocellular carcinoma (HCC), establishing them as the cornerstone of systemic therapy for advanced stages of the disease. Nonetheless, the response rate remains limited, with only 15% to 20% of HCC patients benefiting from ICIs. Approximately 70% to 80% of cases exhibit resistance to anti-PD1 therapy. Therefore, exploring the biomarkers that can be used to identify the response of patients with HCC to immunotherapy and elucidating the potential mechanisms of immunotherapy resistance contribute to the development of predictive biomarkers and are significant for overcoming resistance and enhancing treatment efficacy. This review synthesizes the current understanding of both primary and acquired resistance mechanisms to ICIs in HCC. Compared with existing reviews, this article uniquely integrates the latest evidence on metabolic reprogramming and tumor immune microenvironment (TIME) remodeling in HCC. It also emphasizes the mechanistic crosstalk between oncogenic signaling, immunosuppression, and metabolic adaptation, providing an updated and more comprehensive framework for understanding ICI resistance. It provides a valuable reference for future research aimed at overcoming therapeutic resistance in this malignancy.
免疫检查点抑制剂（ICIs）的出现彻底改变了肝细胞癌（HCC）的治疗模式，使其成为晚期疾病系统性治疗的基石。然而，其应答率仍然有限，仅有15%至20%的HCC患者能从ICIs中获益。约70%至80%的病例表现出对抗PD-1治疗的耐药性。因此，探索可用于识别HCC患者对免疫治疗应答的生物标志物，并阐明免疫治疗耐药的潜在机制，有助于开发预测性生物标志物，对于克服耐药性、提升治疗效果具有重要意义。本综述综合了目前对HCC中ICIs原发性和获得性耐药机制的理解。与现有综述相比，本文独特地整合了关于HCC代谢重编程和肿瘤免疫微环境重塑的最新证据，并强调了致癌信号、免疫抑制与代谢适应之间的机制性交互作用，为理解ICI耐药提供了一个更新、更全面的框架。这为未来旨在克服该恶性肿瘤治疗耐药性的研究提供了有价值的参考。
肿瘤(癌症)患者之家