肝细胞癌靶免治疗药物原发性和继发性耐药后治疗选择

Treatment options after primary or secondary drug resistance to targeted immunotherapy in hepatoellular carcinoma

近年来,针对中晚期肝细胞癌(HCC)的靶向联合免疫治疗取得了显著进展,然而,治疗的有效率仅约为30%,中位无进展生存期为6~9个月,且约20%的病人在初始免疫治疗时即出现耐药现象。对这些耐药病人后续治疗的选择成为了亟待解决的临床问题。靶免联合治疗的失败主要表现为原发性耐药和继发性耐药两种情况。原发性耐药通常与肿瘤免疫原性的降低有关,包括新抗原的低表达、抗原呈递的改变及免疫共抑制信号的表达。继发性耐药则可能与肿瘤在免疫治疗后向低免疫原性表型的克隆进化有关。针对这两种耐药机制的治疗策略目前尚未形成标准的临床方案。HCC的进展模式可以分为肝内进展、肝外进展、肝内新病灶和肝外新病灶,不同进展模式的预后存在显著差异。肝内进展和肝外新病灶的病人相对有较好的进展后生存期,而新发的血管侵犯则预示着较差的预后。未来的临床研究和实践需要在免疫微环境的重编程、病因学差异及多学科诊疗的框架下进行更为精准和个体化的治疗布局,特别是针对耐药HCC病人的后续治疗,可联合局部治疗如肝动脉化疗栓塞(TACE)或肝动脉灌注化疗(HAIC)等,以提高病人的生存期。靶免联合治疗在HCC全病程中的作用正在逐步得到确认,但仍需进一步探索以建立标准的后续治疗策略。

In recent years,significant progress has been made in targeted combined immunotherapy for advanced hepatocellular carcinoma(HCC).However,the treatment response rate remains around 30%,with a median progression-free survival of 6 to 9 months.Additionally,approximately 20%of patients develop resistance to initial immunotherapy,making the selection of subsequent treatment options a critical clinical challenge.The failure of targeted combined immunotherapy primarily manifests as primary resistance and secondary resistance.Primary resistance is often associated with reduced tumor immunogenicity,including low expression of neoantigens,alterations in antigen presentation,and the expression of immune co-inhibitory signals.Secondary resistance may be related to the clonal evolution of the tumor towards a low immunogenicity phenotype following immunotherapy.Currently,there are no standardized clinical strategies to address these resistance mechanisms.The progression patterns of HCC can be categorized into intrahepatic progression,extrahepatic progression,new intrahepatic lesions,and new extrahepatic lesions,with significant differences in prognosis based on these patterns.Patients with intrahepatic progression or new extrahepatic lesions tend to have a relatively favorable post-progression survival,while the presence of new vascular invasion indicates a poor prognosis.Future clinical research and practice must focus on more precise and individualized treatment approaches,considering immune microenvironment reprogramming,etiological differences,and a multidisciplinary treatment framework.Specifically,for HCC patients with drug resistance,combining local treatments such as transarterial chemoembolization(TACE)or hepatic arterial infusion chemotherapy(HAIC)may improve survival outcomes.The role of targeted combined immunotherapy in the overall management of HCC is gradually being recognized,but further exploration is needed to establish standardized post-treatment strategies.