Eghbali Shabnam, Heumann Thatcher Ross
Division of Internal Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Cancers (Basel). 2025 Jan 13;17(2):236. doi: 10.3390/cancers17020236.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and, with only 15-20% of HCC patients being suitable for potentially curative treatments, the vast majority of patients with HCC ultimately require systemic therapy. For decades, the choice of effective systemic therapy for HCC remained sparse. In recent years, after the combination of atezolizumab and bevacizumab demonstrated superior overall survival over the first-line standard, sorafenib, there has been a major therapeutic paradigm shift to immunotherapy-based regimens for HCC. While representing a great leap forward for the treatment of this cancer, the reality is that less than one-third of patients achieve an objective response to immune checkpoint inhibitor-based therapy, so there remains a significant clinical need for further therapeutic optimization. In this review, we provide an overview of the current landscape of immunotherapy for unresectable HCC and delve into the tumor intrinsic and extrinsic mechanisms of resistance to established immunotherapies with a focus on novel therapeutic targets with strong translational potential. Following this, we spotlight emerging immunotherapy approaches and notable clinical trials aiming to optimize immunotherapy efficacy in HCC that include novel immune checkpoint inhibitors, tumor microenvironment modulators, targeted delivery systems, and locoregional interventions.
肝细胞癌（HCC）是全球癌症相关死亡的主要原因，而且由于只有15%-20%的HCC患者适合潜在的治愈性治疗，绝大多数HCC患者最终需要全身治疗。几十年来，用于HCC的有效全身治疗选择一直很少。近年来，在阿替利珠单抗和贝伐单抗联合治疗显示出优于一线标准药物索拉非尼的总生存期后，HCC的治疗模式发生了重大转变，转向基于免疫疗法的方案。虽然这代表了这种癌症治疗的巨大飞跃，但现实情况是，不到三分之一的患者对基于免疫检查点抑制剂的治疗有客观反应，因此临床上仍迫切需要进一步优化治疗。在这篇综述中，我们概述了不可切除HCC免疫治疗的现状，并深入探讨了对现有免疫疗法产生耐药性的肿瘤内在和外在机制，重点关注具有强大转化潜力的新型治疗靶点。在此之后，我们重点介绍新兴的免疫治疗方法和旨在优化HCC免疫治疗疗效的著名临床试验，包括新型免疫检查点抑制剂、肿瘤微环境调节剂、靶向递送系统和局部区域干预措施。
