肝细胞癌的癌症免疫治疗：当前药物策略、耐药、生物标志物及未来方向。
摘要
肝细胞癌（HCC）通常发生于慢性炎症、纤维化且具有免疫耐受性的肝脏中。这一背景塑造了抗肿瘤免疫、 competing liver-related mortality以及后续治疗的可及性。由于肝脏储备功能、疾病病因及区域治疗模式在患者和医疗环境之间存在显著差异，免疫治疗结局也相应具有异质性。免疫检查点抑制剂通过靶向互补的免疫、血管或信号屏障的联合方案，已改变了系统治疗。……
正文 待译
Hepatocellular carcinoma (HCC) usually develops in a chronically inflamed, fibrotic, and immunologically tolerogenic liver. This context shapes antitumor immunity, competing liver-related mortality, and access to subsequent therapy. As hepatic reserve, disease etiology, and regional treatment patterns differ substantially across patients and healthcare settings, immunotherapy outcomes are correspondingly heterogeneous. Immune-checkpoint inhibitors have transformed systemic treatment through combinations that target complementary immune, vascular, or signaling barriers. Atezolizumab plus bevacizumab established combined PD-L1 and VEGF inhibition, whereas STRIDE and nivolumab plus ipilimumab validated dual-checkpoint blockade with distinct CTLA-4 exposure. Camrelizumab plus rivoceranib confirmed the activity of PD-1 and VEGFR2 inhibition. Negative or mixed Phase III trials nevertheless show that biological rationale and higher response rates do not ensure a survival benefit. Immunotherapy is moving into intermediate-stage and perioperative disease, but the updated IMbrave050 findings illustrate the difficulty of achieving durable adjuvant benefit. No validated predictive biomarker currently guides selection among approved regimens. Furthermore, since most HCCs arise in a chronically diseased liver, hepatic reserve and liver-related competing mortality are central determinants of treatment eligibility, tolerance, and survival. This narrative review (literature search through May 31, 2026) is distinguished by its focus on hepatic reserve as a determinant of treatment selection and outcome, and by framing treatment failure as a composite of tumor-driven resistance and liver-related competing mortality. We synthesize evidence on clinical development, resistance, biomarkers, emerging therapies, underrepresented populations, hepatic reserve, and rational subsequent therapy. Further progress will depend on matching defined failure mechanisms to appropriate interventions while preserving hepatic reserve. Hepatocellular carcinoma (HCC) is a common liver cancer that often develops in a liver already damaged by chronic inflammation, fibrosis, or cirrhosis. This damaged liver makes treatment more complex because doctors must control the cancer while preserving liver function. Immune checkpoint inhibitors, a type of immunotherapy, have changed treatment for advanced HCC, especially when combined with other drugs that target blood vessel growth or different immune checkpoints. However, not all combinations work equally well, and they are not interchangeable. Some patients benefit greatly, but many eventually experience cancer progression or suffer from worsening liver function. This review summarizes the current evidence on immunotherapy for HCC, focusing on why treatment failure should be seen as both cancer resistance and liver-related complications. We discuss how the liver’s immune environment, tumor blood vessels, and different checkpoint pathways influence treatment response. We also review biomarkers that may help select treatments, though none are yet validated for choosing among approved regimens. We highlight the importance of liver reserve—the liver’s remaining functional capacity—as a key factor in treatment decisions. Finally, we outline future research priorities: testing biomarkers in randomized trials, comparing treatment sequences, developing new therapies based on specific resistance mechanisms, and preserving liver function throughout treatment. This review is intended for clinicians and researchers who want a balanced, evidence-based overview of immunotherapy in HCC, with a particular emphasis on the liver as a critical organ that shapes both treatment outcomes and patient survival.
English
Hepatocellular carcinoma (HCC) usually develops in a chronically inflamed, fibrotic, and immunologically tolerogenic liver. This context shapes antitumor immunity, competing liver-related mortality, and access to subsequent therapy. As hepatic reserve, disease etiology, and regional treatment patterns differ substantially across patients and healthcare settings, immunotherapy outcomes are correspondingly heterogeneous. Immune-checkpoint inhibitors have transformed systemic treatment through combinations that target complementary immune, vascular, or signaling barriers.…