The tyrosine kinase inhibitor (TKI) sorafenib continues to be the anchor drug in the treatment of advanced stage hepatocellular carcinoma (HCC). Other TKIs as well as immune checkpoint inhibitors (ICIs) have also been approved, however the response rates remain poor and heterogeneous among HCC patients, largely due to antitumor drug resistance. Studies aimed at identifying novel biomarkers and developing new strategies to improve the response to current treatment and to overcome drug resistance, are urgently needed. Germline or somatic mutations, neoantigens, and an immunotolerogenic state against constant inflammatory stimuli in the liver, are crucial for the anti-tumor response. A pharmacogenetic approach has been attempted considering germline polymorphisms in genes encoding for proteins involved in drug-targeted pathways. Single gene and comprehensive multi-gene somatic profiling approaches have been adopted in HCC to identify tumor sensitivity scores and immunogenic profiles that can be exploited for new biomarkers and innovative therapeutic approaches. However, the high genomic heterogeneity of tumors and lack of molecularly targeted agents, hamper the discovery of specific molecular markers of resistance to therapy. Adoptive cell therapy with chimeric antigen receptor redirected T (CAR-T) cells targeting specific tumor-associated antigens (TAAs) was proposed recently. The specificity of the chosen TAA, an efficient homing of CAR-T cells to the tumor site, and the ability of CAR-T cells to survive in the tumor microenvironment are central factors in the success of CAR-T therapy.

The current review describes the principal systemic treatments for HCC and the molecular evidence regarding potential predictive host and somatic genetic markers, as well as the emerging strategy of liquid biopsy for disease monitoring. Novel immunotherapeutic approaches for HCC treatment, including the use of ICIs and CAR-T, as well as strategies to overcome drug resistance, are discussed.

酪氨酸激酶抑制剂（TKI）索拉非尼继续是晚期肝细胞癌（HCC）治疗的主要药物。其他TKI以及免疫检查点抑制剂（ICI）也已获得批准，但是HCC患者的反应率仍然很差且异质，这主要是由于抗肿瘤药耐药性。迫切需要进行旨在鉴定新的生物标记物并开发新策略以改善对当前治疗的反应并克服耐药性的研究。生殖细胞或体细胞突变，新抗原以及针对肝脏中持续不断的炎症刺激的免疫耐受状态对于抗肿瘤反应至关重要。考虑到编码涉及药物靶向途径的蛋白质的基因中的种系多态性，已经尝试了一种药物遗传学方法。HCC已采用单基因和全面的多基因体谱分析方法来鉴定肿瘤敏感性评分和免疫原性谱，可将其用于新的生物标志物和创新的治疗方法。然而，肿瘤的高基因组异质性和缺乏分子靶向药物，阻碍了对治疗耐药性的特定分子标记的发现。最近提出了采用嵌合抗原受体重定向的T（CAR-T）细胞靶向特定肿瘤相关抗原（TAA）的过继细胞疗法。所选TAA的特异性，CAR-T细胞在肿瘤部位的有效归巢以及CAR-T细胞在肿瘤微环境中生存的能力是CAR-T治疗成功的关键因素。

本综述描述了肝癌的主要全身治疗方法以及有关潜在的预测宿主和体细胞遗传标志物的分子证据，以及用于疾病监测的液体活检的新兴策略。讨论了用于HCC治疗的新型免疫治疗方法，包括使用ICI和CAR-T以及克服耐药性的策略。