The advent of immune checkpoint inhibitors, particularly monoclonal antibodies (mAbs) that target the programmed cell death protein 1 (PD-1) or its ligand (PD-L1), has revolutionised cancer treatment across various malignancies. Despite this groundbreaking progress, a considerable cohort of patients fails to derive benefit from anti-PD(L)1 mAb therapy due to primary and secondary resistance mechanisms. The percentage of patients who respond to these treatments varies among different tumour types, ranging from 40% in more sensitive tumours, like metastatic melanoma, to virtually zero in less sensitive tumours such as glioblastoma.1 Hepatocellular carcinoma (HCC), one of the deadliest solid tumours, emerges as a moderately sensitive tumour, where monotherapy with anti-PD(L)1 agents demonstrates a response in only about 15% of cases.2 These encouraging yet constrained clinical outcomes have elevated immunotherapy to a pivotal status in clinical practice, instigating evaluations of combinatory approaches with other agents alongside anti-PD(L)1 mAbs to circumvent resistance mechanisms constraining monotherapies. Among the various combinations evaluated in clinical trials, those that have stood out for their positive results include the combination of anti-PD(L)1 mAb with the antiangiogenic agent, bevacizumab3 or with other immune checkpoint inhibitor, anti-CTLA-4 mAb,4 becoming the first-line systemic treatment options for HCC patients. However, new therapeutic targets are necessary …

中文翻译：

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靶向金属蛋白酶是一种有前途的策略，可通过克服肝细胞癌的免疫排斥来增强免疫治疗反应

免疫检查点抑制剂的出现，特别是针对程序性细胞死亡蛋白 1 (PD-1) 或其配体 (PD-L1) 的单克隆抗体 (mAb)，彻底改变了各种恶性肿瘤的癌症治疗。尽管取得了这一突破性进展，但由于原发性和继发性耐药机制，相当多的患者未能从抗 PD(L)1 mAb 治疗中获益。不同肿瘤类型对这些治疗有反应的患者比例各不相同，从转移性黑色素瘤等较敏感的肿瘤中为 40%，到胶质母细胞瘤等不太敏感的肿瘤中几乎为零。1 肝细胞癌 (HCC)，最致命的癌症之一实体瘤是一种中度敏感的肿瘤，抗 PD(L)1 药物单一疗法仅对约 15% 的病例有反应。2 这些令人鼓舞但又有限的临床结果已将免疫疗法提升到临床实践中的关键地位，鼓励评估与其他药物以及抗 PD(L)1 mAb 的组合方法，以规避限制单一疗法的耐药机制。在临床试验中评估的各种组合中，那些取得积极成果的组合包括抗PD(L)1 mAb与抗血管生成剂贝伐珠单抗3或与其他免疫检查点抑制剂抗CTLA-4 mAb的组合， 4成为HCC患者的一线系统治疗选择。然而，新的治疗靶点是必要的……