Liver cancer is one of the most prevalent cancers, and the third most common cause of cancer-related mortality worldwide. The therapeutic options for the main types of primary liver cancer—hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA)—are very limited. HCC and CCA are immunogenic cancers, but effective immune-mediated tumour control is prevented by their immunosuppressive tumour microenvironment. Despite the critical involvement of key co-inhibitory immune checkpoint interactions in immunosuppression in liver cancer, only a minority of patients with HCC respond to monotherapy using approved checkpoint inhibitor antibodies. To develop effective (combinatorial) therapeutic immune checkpoint strategies for liver cancer, in-depth knowledge of the different mechanisms that contribute to intratumoral immunosuppression is needed. Here, we review the co-inhibitory pathways that are known to suppress intratumoral T cells in HCC and CCA. We provide a detailed description of insights from preclinical studies in cellular crosstalk within the tumour microenvironment that results in interactions between co-inhibitory receptors on different T-cell subsets and their ligands on other cell types, including tumour cells. We suggest alternative immune checkpoints as promising targets, and draw attention to the possibility of combined targeting of co-inhibitory and co-stimulatory pathways to abrogate immunosuppression.

肝癌是最普遍的癌症之一，也是全世界癌症相关死亡的第三大常见原因。主要类型的原发性肝癌——肝细胞癌 (HCC) 和胆管癌 (CCA)——的治疗选择非常有限。HCC 和 CCA 是免疫原性癌症，但它们的免疫抑制肿瘤微环境阻碍了有效的免疫介导的肿瘤控制。尽管关键的共抑制免疫检查点相互作用在肝癌免疫抑制中起关键作用，但只有少数 HCC 患者对使用经批准的检查点抑制剂抗体的单一疗法有反应。为了开发针对肝癌的有效（组合）治疗性免疫检查点策略，需要深入了解有助于肿瘤内免疫抑制的不同机制。这里，我们回顾了已知抑制 HCC 和 CCA 肿瘤内 T 细胞的共抑制途径。我们详细描述了肿瘤微环境中细胞串扰的临床前研究的见解，这些串扰导致不同 T 细胞亚群上的共抑制受体与其在其他细胞类型（包括肿瘤细胞）上的配体之间的相互作用。我们建议将替代免疫检查点作为有希望的目标，并提请注意联合靶向共抑制和共刺激途径以消除免疫抑制的可能性。我们详细描述了肿瘤微环境中细胞串扰的临床前研究的见解，这些串扰导致不同 T 细胞亚群上的共抑制受体与其在其他细胞类型（包括肿瘤细胞）上的配体之间的相互作用。我们建议将替代免疫检查点作为有希望的目标，并提请注意联合靶向共抑制和共刺激途径以消除免疫抑制的可能性。我们详细描述了肿瘤微环境中细胞串扰的临床前研究的见解，这些串扰导致不同 T 细胞亚群上的共抑制受体与其在其他细胞类型（包括肿瘤细胞）上的配体之间的相互作用。我们建议将替代免疫检查点作为有希望的目标，并提请注意联合靶向共抑制和共刺激途径以消除免疫抑制的可能性。